Skip to main content
SpringerLink
Log in

Parkinson’s Disease: Basic Pathomechanisms and a Clinical Overview

  • Chapter
  • First Online:
Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

Abstract

PD is a common and a debilitating degenerative movement disorder. The number of patients is increasing worldwide and as yet there is no cure for the disease. The majority of existing treatments target motor symptom control. Over the last two decades the impact of the genetic contribution to PD has been appreciated. Significant discoveries have been made, which have advanced our understanding of the pathophysiological and molecular basis of PD. In this chapter we outline current knowledge of the clinical aspects of PD and the basic mechanistic understanding.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

8-OHDG:

8-Hydroxy-2-deoxyguanosine

APOE:

Apolipoprotein E

ATP13a2:

ATPase 13a2

COMT:

Catechol-O-methyl transferase

CT:

Computed tomography

DAergic:

Dopaminergic

DAT:

Dopamine transporter

DaTSCAN:

Dopamine transporter scan

DaTSPECT:

Dopamine transporter single photon emission computed tomography

DLB:

Dementia with Lewy bodies

DMV:

Dorsal motor nuclear complex of cranial nerves IX and X

EDS:

Excessive daytime sleepiness

GABA:

Gamma-aminobutyric acid

GBA:

Glucocerebrosidase beta acid

GD:

Gaucher’s disease

HNE:

4hydroxy2-nonenal

IL1:

Interleukin1

iNOS:

Inducible nitric oxide synthase

iPS:

Induced pluripotent stem cell

LBs:

Lewy bodies

LN:

Lewy neurite

LRRK2:

Leucine-rich-repeat kinase 2

MAO:

Monoamine oxidase

MAOI:

Monoamine oxidase inhibitor

MAPT:

Microtubule-associated protein tau

MCI:

Mild cognitive impairment

MIBG:

123-meta iodobenzylguanidine radioactive tracer

MR:

Magnetic resonance

MSA:

Multiple system atrophy

NAC:

Non-amyloid component

ND:

Nigral degeneration

NFTs:

Neurofibrillary tangles

PD:

Parkinson’s disease

PDD:

PD dementia

PET:

Positron emission tomography

PSP:

Progressive supranuclear palsy

QSBB:

Queen Square Brain Bank

RBD:

REM sleep behaviour disorder

REM:

Rapid eye movement

RIPK:

Receptor interacting protein kinase

ROS:

Reactive oxygen species

SN:

Substantia nigra

SNCA:

Alpha-synuclein

SWEDD:

Scans without evidence of dopamine deficit

TNF:

Tumour necrosis factor

TREM2:

Triggering receptor expressed on myeloid cells

UCHL1:

Ubiquitin C-terminal hydrolase L1

UPDRS:

Unified Parkinson’s disease rating scale

UPS:

Ubiquitin proteasome system

VPS35:

Vaboular protein sorting-associated protein 35

References

  1. MacDonald BK, Cockerell OC, Sander JW, Shorvon SD (2000) The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain J Neurol 123(Pt 4):665–676. PMID: 10733998.

    Article  Google Scholar 

  2. de Rijk MC, Breteler MM, Graveland GA, Ott A, Grobbee DE, van der Meche FG et al (1995) Prevalence of Parkinson's disease in the elderly: the Rotterdam Study. Neurology 45(12):2143–2146. PMID: 8848182.

    Article  PubMed  Google Scholar 

  3. Findley LJ (2007) The economic impact of Parkinson's disease. Parkinsonism Relat Disord 13(Suppl):S8–S12. PMID: 17702630.

    Article  PubMed  Google Scholar 

  4. GBD 2013 Mortality and Causes of Death Collaborators (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385(9963):117–171. PMID: 25530442. PMCID: 4340604

    Article  Google Scholar 

  5. Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51(6):745–752. PMID: 2841426. PMCID: 1033142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain J Neurol 114(Pt 5):2283–2301. PMID: 1933245.

    Article  Google Scholar 

  7. Sieber BA, Landis S, Koroshetz W, Bateman R, Siderowf A, Galpern WR et al (2014) Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference. Ann Neurol 76(4):469–472. PMID: 25164235.

    Article  PubMed  Google Scholar 

  8. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46(9):989–993. PMID: 25064009. PMCID: 4146673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Klein C, Westenberger A (2012) Genetics of Parkinson's disease. Cold Spring Harb Perspect Med 2(1):a008888. PMID: 22315721. PMCID: 3253033

    Article  PubMed  PubMed Central  Google Scholar 

  10. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simon-Sanchez J et al (2012) Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum Mol Genet 21(22):4996–5009. PMID: 22892372. PMCID: 3576713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T et al (2013) Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain J Neurol 136(Pt 2):392–399. PMID: 23413260.

    Article  Google Scholar 

  12. Ritz B, Rhodes SL, Bordelon Y, Bronstein J (2012) alpha-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease. PLoS One 7(5):e36199. PMID: 22615757. PMCID: 3352914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T, Giladi N, Orr-Urtreger A (2012) The age at motor symptoms onset in LRRK2-associated Parkinson's disease is affected by a variation in the MAPT locus: a possible interaction. J Mol Neurosci 46(3):541–544. PMID: 21898123.

    Article  CAS  PubMed  Google Scholar 

  14. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7(7):583–590. PMID: 18539534. PMCID: 2832754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Farrer MJ, Stone JT, Lin CH, Dachsel JC, Hulihan MM, Haugarvoll K et al (2007) Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 13(2):89–92. PMID: 17222580.

    Article  PubMed  Google Scholar 

  16. Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME, Wong K et al (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79(2):104–109. PMID: 12809640.

    Article  CAS  PubMed  Google Scholar 

  17. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004) Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 351(19):1972–1977. PMID: 15525722

    Article  CAS  PubMed  Google Scholar 

  18. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 361(17):1651–1661. PMID: 19846850. PMCID: 2856322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ et al (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 72(6):893–901. PMID: 23071076. PMCID: 3556649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gatto NM, Cockburn M, Bronstein J, Manthripragada AD, Ritz B (2009) Well-water consumption and Parkinson's disease in rural California. Environ Health Perspect 117(12):1912–1918. PMID: 20049211. PMCID: 2799466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A et al (2007) Pesticide exposure and self-reported Parkinson's disease in the agricultural health study. Am J Epidemiol 165(4):364–374. PMID: 17116648

    Article  CAS  PubMed  Google Scholar 

  22. Baldi I, Cantagrel A, Lebailly P, Tison F, Dubroca B, Chrysostome V et al (2003) Association between Parkinson's disease and exposure to pesticides in southwestern France. Neuroepidemiology 22(5):305–310. PMID: 12902626

    Article  PubMed  Google Scholar 

  23. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J et al (2007) Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study. Occup Environ Med 64(10):666–672. PMID: 17332139. PMCID: 2078401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pezzoli G, Cereda E (2013) Exposure to pesticides or solvents and risk of Parkinson disease. Neurology 80(22):2035–2041. PMID: 23713084

    Article  CAS  PubMed  Google Scholar 

  25. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain J Neurol 136(Pt 1):43–64. PMID: 23208308. PMCID: 3624697

    Article  Google Scholar 

  26. Gardner RC, Burke JF, Nettiksimmons J, Goldman S, Tanner CM, Yaffe K (2015) Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurol 77(6):987–995. PMID: 25726936. PMCID: 4447556

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen H, Mosley TH, Alonso A, Huang X (2009) Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 169(9):1064–1069. PMID: 19299404. PMCID: 2727240

    Article  PubMed  PubMed Central  Google Scholar 

  28. Weisskopf MG, O'Reilly E, Chen H, Schwarzschild MA, Ascherio A (2007) Plasma urate and risk of Parkinson's disease. Am J Epidemiol 166(5):561–567. PMID: 17584757. PMCID: 2391073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Simon KC, Eberly S, Gao X, Oakes D, Tanner CM, Shoulson I et al (2014) Mendelian randomization of serum urate and parkinson disease progression. Ann Neurol 76(6):862–868. PMID: 25257975. PMCID: 4245314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE et al (2011) Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies. Cochrane Database Syst Rev 11:CD008454. PMID: 22071848

    Google Scholar 

  31. Gao X, Simon KC, Schwarzschild MA, Ascherio A (2012) Prospective study of statin use and risk of Parkinson disease. Arch Neurol 69(3):380–384. PMID: 22410446. PMCID: 3398841

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chaudhuri KR, Healy DG, Schapira AH (2006) National Institute for Clinical E. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 5(3):235–245. PMID: 16488379

    Article  PubMed  Google Scholar 

  33. Gallagher DA, Lees AJ, Schrag A (2010) What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? Mov Disord 25(15):2493–2500. PMID: 20922807

    Article  PubMed  Google Scholar 

  34. Norlinah IM, Bhatia KP, Ostergaard K, Howard R, Arabia G, Quinn NP (2007) Primary lateral sclerosis mimicking atypical parkinsonism. Mov Disord 22(14):2057–2062. PMID: 17702034

    Article  PubMed  Google Scholar 

  35. Ling H, Massey LA, Lees AJ, Brown P, Day BL (2012) Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease. Brain J Neurol 135(Pt 4):1141–1153. PMID: 22396397. PMCID: 3326257

    Article  Google Scholar 

  36. Lees AJ, Hardy J, Revesz T (2009) Parkinson's disease. Lancet 373(9680):2055–2066. PMID: 19524782

    Article  CAS  PubMed  Google Scholar 

  37. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P et al (2008) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23(15):2129–2170. PMID: 19025984

    Article  PubMed  Google Scholar 

  38. Schrag A, Quinn N (2000) Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study. Brain J Neurol 123(Pt 11):2297–2305. PMID: 11050029

    Article  Google Scholar 

  39. Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson's disease. J Neurol Neurosurg Psychiatry 62(5):436–446. PMID: 9153598. PMCID: 486843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters E, Berendse HW (2004) Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann Neurol 56(2):173–181. PMID: 15293269

    Article  PubMed  Google Scholar 

  41. Sommer U, Hummel T, Cormann K, Mueller A, Frasnelli J, Kropp J et al (2004) Detection of presymptomatic Parkinson's disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 19(10):1196–1202. PMID: 15390014

    Article  PubMed  Google Scholar 

  42. Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K et al (2008) Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 63(2):167–173. PMID: 18067173

    Article  PubMed  Google Scholar 

  43. Silveira-Moriyama L, Guedes LC, Kingsbury A, Ayling H, Shaw K, Barbosa ER et al (2008) Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 71(13):1021–1026. PMID: 18809839

    Article  CAS  PubMed  Google Scholar 

  44. Gaig C, Vilas D, Infante J, Sierra M, Garcia-Gorostiaga I, Buongiorno M et al (2014) Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease. PLoS One 9(10):e108982. PMID: 25330404. PMCID: 4201457

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Khan NL, Katzenschlager R, Watt H, Bhatia KP, Wood NW, Quinn N et al (2004) Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 62(7):1224–1226. PMID: 15079034

    Article  CAS  PubMed  Google Scholar 

  46. Postuma RB, Iranzo A, Hogl B, Arnulf I, Ferini-Strambi L, Manni R et al (2015) Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study. Ann Neurol 77(5):830–839. PMID: 25767079

    Article  PubMed  Google Scholar 

  47. Gagnon JF, Vendette M, Postuma RB, Desjardins C, Massicotte-Marquez J, Panisset M et al (2009) Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease. Ann Neurol 66(1):39–47. PMID: 19670440

    Article  PubMed  Google Scholar 

  48. Chen JJ, Marsh L (2014) Anxiety in Parkinson's disease: identification and management. Ther Adv Neurol Disord 7(1):52–59. PMID: 24409202. PMCID: 3886380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Adams-Carr KL, Bestwick JP, Shribman S, Lees A, Schrag A, Noyce AJ (2015) Constipation preceding Parkinson's disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 7. PMID: 26345189

    Google Scholar 

  50. Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J et al (2014) Accumulation of alpha-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease. Acta Neuropathol 127(2):235–241. PMID: 24240814

    Article  CAS  PubMed  Google Scholar 

  51. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676. PMID: 18725592. PMCID: 2676993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Svenningsson P, Westman E, Ballard C, Aarsland D (2012) Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol 11(8):697–707. PMID: 22814541

    Article  PubMed  Google Scholar 

  53. Evans JR, Mason SL, Williams-Gray CH, Foltynie T, Brayne C, Robbins TW et al (2011) The natural history of treated Parkinson's disease in an incident, community based cohort. J Neurol Neurosurg Psychiatry 82(10):1112–1118. PMID: 21593513

    Article  PubMed  Google Scholar 

  54. Gratwicke J, Jahanshahi M, Foltynie T (2015) Parkinson's disease dementia: a neural networks perspective. Brain J Neurol 138(Pt 6):1454–1476. PMID: 25888551. PMCID: 4614131

    Article  Google Scholar 

  55. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65(12):1863–1872. PMID: 16237129

    Article  CAS  PubMed  Google Scholar 

  56. Fenelon G, Mahieux F, Huon R, Ziegler M (2000) Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Brain J Neurol 123(Pt 4):733–745. PMID: 10734005

    Article  Google Scholar 

  57. Williams-Gray CH, Foltynie T, Lewis SJ, Barker RA (2006) Cognitive deficits and psychosis in Parkinson's disease: a review of pathophysiology and therapeutic options. CNS Drugs 20(6):477–505. PMID: 16734499

    Article  CAS  PubMed  Google Scholar 

  58. Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J et al (2010) Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 75(12):1062–1069. PMID: 20855849. PMCID: 2942065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Litvan I, Goldman JG, Troster AI, Schmand BA, Weintraub D, Petersen RC et al (2012) Diagnostic criteria for mild cognitive impairment in Parkinson's disease: movement disorder society task force guidelines. Mov Disord 27(3):349–356. PMID: 22275317. PMCID: 3641655

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW et al (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72(1):100–105. PMID: 25401511. PMCID: 4399368

    Article  PubMed  PubMed Central  Google Scholar 

  61. Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain J Neurol 132(Pt 7):1783–1794. PMID: 19286695. PMCID: 2702833

    Article  Google Scholar 

  62. Alcalay RN, Caccappolo E, Mejia-Santana H, Tang M, Rosado L, Orbe Reilly M et al (2012) Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 78(18):1434–1440. PMID: 22442429. PMCID: 3345785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. (CG35) Ng (2006) Parkinson's disease in over 20's: diagnosis and management. niceorguk/guidance/cg35

    Google Scholar 

  64. Massey LA, Micallef C, Paviour DC, O'Sullivan SS, Ling H, Williams DR et al (2012) Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. Mov Disord 27(14):1754–1762. PMID: 22488922

    Article  PubMed  Google Scholar 

  65. Berg D, Godau J, Walter U (2008) Transcranial sonography in movement disorders. Lancet Neurol 7(11):1044–1055. PMID: 18940694

    Article  PubMed  Google Scholar 

  66. Brooks DJ (2010) Imaging approaches to Parkinson disease. J Nucl Med 51(4):596–609. PMID: 20351351

    Article  CAS  PubMed  Google Scholar 

  67. Bajaj N, Hauser RA, Grachev ID (2013) Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes. J Neurol Neurosurg Psychiatry 84(11):1288–1295. PMID: 23486993. PMCID: 3812862

    Article  PubMed  PubMed Central  Google Scholar 

  68. Erro R, Schneider SA, Stamelou M, Quinn NP, Bhatia KP (2015) What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies. J Neurol Neurosurg Psychiatry 19. PMID: 25991401

    Google Scholar 

  69. Jellinger KA (2012) Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts. Mov Disord 27(1):8–30. PMID: 22081500

    Article  CAS  PubMed  Google Scholar 

  70. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH et al (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain J Neurol 136(Pt 8):2419–2431. PMID: 23884810. PMCID: 3722357

    Article  Google Scholar 

  71. Dickson DW (2012) Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med 2(8.) PMID: 22908195. PMCID: 3405828

    Google Scholar 

  72. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840. PMID: 9278044

    Article  CAS  PubMed  Google Scholar 

  73. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol 99(1):14–20. PMID: 10651022

    Article  CAS  PubMed  Google Scholar 

  74. Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathol 114(3):231–241. PMID: 17576580

    Article  CAS  PubMed  Google Scholar 

  75. McCann H, Cartwright H, Halliday GM (2015) Neuropathology of alpha-synuclein propagation and braak hypothesis. Mov Disord 4. PMID: 26340605

    Google Scholar 

  76. Orimo S, Uchihara T, Kanazawa T, Itoh Y, Wakabayashi K, Kakita A et al (2011) Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease. Neuropathol Appl Neurobiol 37(7):791–802. PMID: 21696416

    Article  CAS  PubMed  Google Scholar 

  77. Matzuk MM, Saper CB (1985) Preservation of hypothalamic dopaminergic neurons in Parkinson's disease. Ann Neurol 18(5):552–555. PMID: 4073850

    Article  CAS  PubMed  Google Scholar 

  78. Double KL, Reyes S, Werry EL, Halliday GM (2010) Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions? Prog Neurobiol 92(3):316–329. PMID: 20541584

    Article  CAS  PubMed  Google Scholar 

  79. Phani S, Loike JD, Przedborski S (2012) Neurodegeneration and inflammation in Parkinson's disease. Parkinsonism Relat Disord 18(Suppl 1):S207–S209. PMID: 22166436

    Article  PubMed  Google Scholar 

  80. Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74(12):995–1002. PMID: 20308684. PMCID: 2848103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Paumier KL, Sukoff Rizzo SJ, Berger Z, Chen Y, Gonzales C, Kaftan E et al (2013) Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease. PLoS One 8(8):e70274. PMID: 23936403. PMCID: 3731353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24(2):197–211. PMID: 12498954

    Article  PubMed  Google Scholar 

  83. Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 115(4):399–407. PMID: 18297293. PMCID: 2270355

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2009) Evidence against a reliable staging system of alpha-synuclein pathology in Parkinson's disease. Neuropathol Appl Neurobiol 35(1):125–126. PMID: 19187066

    Article  CAS  PubMed  Google Scholar 

  85. Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 396(1):67–72. PMID: 16330147

    Article  CAS  PubMed  Google Scholar 

  86. Lebouvier T, Chaumette T, Damier P, Coron E, Touchefeu Y, Vrignaud S et al (2008) Pathological lesions in colonic biopsies during Parkinson's disease. Gut 57(12):1741–1743. PMID: 19022934

    Article  CAS  PubMed  Google Scholar 

  87. Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117(6):613–634. PMID: 19399512. PMCID: 2757320

    Article  PubMed  PubMed Central  Google Scholar 

  88. Houlden H, Singleton AB (2012) The genetics and neuropathology of Parkinson's disease. Acta Neuropathol 124(3):325–338. PMID: 22806825. PMCID: 3589971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL et al (2013) A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80(11):1062–1064. PMID: 23427326. PMCID: 3653201

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P et al (2013) alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathol 125(5):753–769. PMID: 23404372. PMCID: 3681325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lesage S, Anheim M, Letournel F, Bousset L, Honore A, Rozas N et al (2013) G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 73(4):459–471. PMID: 23526723

    Article  CAS  PubMed  Google Scholar 

  92. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B et al (2013) Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord 28(6):811–813. PMID: 23457019

    Article  CAS  PubMed  Google Scholar 

  93. Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J et al (2014) Novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol Aging 35(9):2180 e1–2180 e5. PMID: 24746362

    Article  CAS  Google Scholar 

  94. Poulopoulos M, Levy OA, Alcalay RN (2012) The neuropathology of genetic Parkinson's disease. Mov Disord 27(7):831–842. PMID: 22451330. PMCID: 3383342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kiely AP, Ling H, Asi YT, Kara E, Proukakis C, Schapira AH et al (2015) Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Mol Neurodegener 10:41. PMID: 26306801. PMCID: 4549856

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Tokutake T, Ishikawa A, Yoshimura N, Miyashita A, Kuwano R, Nishizawa M et al (2014) Clinical and neuroimaging features of patient with early-onset Parkinson's disease with dementia carrying SNCA p.G51D mutation. Parkinsonism Relat Disord 20(2):262–264. PMID: 24315198

    Article  PubMed  Google Scholar 

  97. Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH et al (2000) Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99(6):663–672. PMID: 10867800

    Article  CAS  PubMed  Google Scholar 

  98. Obi T, Nishioka K, Ross OA, Terada T, Yamazaki K, Sugiura A et al (2008) Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 70(3):238–241. PMID: 18195271

    Article  CAS  PubMed  Google Scholar 

  99. Cookson MR (2015) LRRK2 pathways leading to neurodegeneration. Curr Neurol Neurosci Rep 15(7):42. PMID: 26008812

    Article  PubMed  CAS  Google Scholar 

  100. Wallings R, Manzoni C, Bandopadhyay R (2015) Cellular processes associated with LRRK2 function and dysfunction. FEBS J 282(15):2806–2826. PMID: 25899482. PMCID: 4522467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lee BD, Dawson VL, Dawson TM (2012) Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease. Trends Pharmacol Sci 33(7):365–373. PMID: 22578536. PMCID: 3383378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Deng X, Dzamko N, Prescott A, Davies P, Liu Q, Yang Q et al (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 7(4):203–205. PMID: 21378983. PMCID: 3287420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Taymans JM, Greggio E (2015) LRRK2 kinase inhibition as a therapeutic strategy for Parkinson's disease, where do we stand? Curr Neuropharmacol 14(3):214–225. PMID: 26517051

    Article  Google Scholar 

  104. Wider C, Dickson DW, Wszolek ZK (2010) Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegener Dis 7(1-3):175–179. PMID: 20197701. PMCID: 2859237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Covy JP, Yuan W, Waxman EA, Hurtig HI, Van Deerlin VM, Giasson BI (2009) Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Mov Disord 24(1):32–39. PMID: 19006185. PMCID: 2634827

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ et al (2004) Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62(9):1619–1622. PMID: 15136696

    Article  CAS  PubMed  Google Scholar 

  107. Ling H, Kara E, Bandopadhyay R, Hardy J, Holton J, Xiromerisiou G et al (2013) TDP-43 pathology in a patient carrying G2019S LRRK2 mutation and a novel p.Q124E MAPT. Neurobiol Aging 34(12):2889 e5–2889 e9. PMID: 23664753. PMCID: 3906605

    Article  CAS  Google Scholar 

  108. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T et al (2000) Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 342(21):1560–1567. PMID: 10824074

    Article  CAS  PubMed  Google Scholar 

  109. Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE et al (2013) Parkin disease: a clinicopathologic entity? JAMA Neurol 70(5):571–579. PMID: 23459986. PMCID: 4202385

    Article  PubMed  PubMed Central  Google Scholar 

  110. Samaranch L, Lorenzo-Betancor O, Arbelo JM, Ferrer I, Lorenzo E, Irigoyen J et al (2010) PINK1-linked parkinsonism is associated with Lewy body pathology. Brain J Neurol 133(Pt 4):1128–1142. PMID: 20356854

    Article  Google Scholar 

  111. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E (2004) Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 81(1):70–73. PMID: 14728994

    Article  CAS  PubMed  Google Scholar 

  112. Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW et al (2012) Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 72(3):455–463. PMID: 23034917. PMCID: 3638323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Clark LN, Ross BM, Wang Y, Mejia-Santana H, Harris J, Louis ED et al (2007) Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69(12):1270–1277. PMID: 17875915. PMCID: 3624967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Goker-Alpan O, Stubblefield BK, Giasson BI, Sidransky E (2010) Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol 120(5):641–649. PMID: 20838799. PMCID: 3352317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson's disease. J Parkinsons Dis 3(4):461–491. PMID: 24252804. PMCID: 4135313

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Sanders LH, Greenamyre JT (2013) Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 62:111–120. PMID: 23328732. PMCID: 3677955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Xiang W, Schlachetzki JC, Helling S, Bussmann JC, Berlinghof M, Schaffer TE et al (2013) Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Mol Cell Neurosci 54:71–83. PMID: 23369945

    Article  CAS  PubMed  Google Scholar 

  118. Giasson BI, Lee VM (2003) Are ubiquitination pathways central to Parkinson's disease? Cell 114(1):1–8. PMID: 12859888

    Article  CAS  PubMed  Google Scholar 

  119. Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD et al (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain J Neurol 127(Pt 2):420–430. PMID: 14662519

    Article  Google Scholar 

  120. Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE et al (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281(16):10816–10824. PMID: 16517609. PMCID: 1850953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mamais A, Chia R, Beilina A, Hauser DN, Hall C, Lewis PA et al (2014) Arsenite stress down-regulates phosphorylation and 14-3-3 binding of leucine-rich repeat kinase 2 (LRRK2), promoting self-association and cellular redistribution. J Biol Chem 289(31):21386–21400. PMID: 24942733. PMCID: 4118103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Seet RC, Lee CY, Lim EC, Tan JJ, Quek AM, Chong WL et al (2010) Oxidative damage in Parkinson disease: measurement using accurate biomarkers. Free Radic Biol Med 48(4):560–566. PMID: 19969070

    Article  CAS  PubMed  Google Scholar 

  123. Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K (2007) Oxidative damage in nucleic acids and Parkinson's disease. J Neurosci Res 85(5):919–934. PMID: 17279544

    Article  CAS  PubMed  Google Scholar 

  124. Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley KE et al (2014) Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease. Neurobiol Aging 35(5):1111–1115. PMID: 24300239. PMCID: 3969149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Barrett PJ, Timothy GJ (2015) Post-translational modification of alpha-synuclein in Parkinsons disease. Brain Res 14. PMID: 26080075

    Google Scholar 

  126. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8(6):600–606. PMID: 12042811

    Article  CAS  PubMed  Google Scholar 

  127. Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804–2815. PMID: 3411354

    CAS  PubMed  Google Scholar 

  128. Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17–37. PMID: 17623039

    CAS  PubMed  Google Scholar 

  129. Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE (2013) alpha-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol 73(2):155–169. PMID: 23225525. PMCID: 3608838

    Article  CAS  PubMed  Google Scholar 

  130. Hoffman-Zacharska D, Koziorowski D, Ross OA, Milewski M, Poznanski J, Jurek M et al (2013) Novel A18T and pA29S substitutions in alpha-synuclein may be associated with sporadic Parkinson's disease. Parkinsonism Relat Disord 19(11):1057–1060. PMID: 23916651. PMCID: 4055791

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rutherford NJ, Moore BD, Golde TE, Giasson BI (2014) Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of alpha-synuclein. J Neurochem 131(6):859–867. PMID: 24984882

    Article  CAS  PubMed  Google Scholar 

  132. Bartels T, Choi JG, Selkoe DJ (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107–110. PMID: 21841800. PMCID: 3166366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Saxena S, Caroni P (2011) Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71(1):35–48. PMID: 21745636

    Article  CAS  PubMed  Google Scholar 

  134. Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N et al (2012) An antibody with high reactivity for disease-associated alpha-synuclein reveals extensive brain pathology. Acta Neuropathol 124(1):37–50. PMID: 22370907

    Article  CAS  PubMed  Google Scholar 

  135. Sengupta U, Guerrero-Munoz MJ, Castillo-Carranza DL, Lasagna-Reeves CA, Gerson JE, Paulucci-Holthauzen AA et al (2015) Pathological interface between oligomeric alpha-synuclein and tau in synucleinopathies. Biol Psychiatry 78(10):672–683. PMID: 25676491

    Article  CAS  PubMed  Google Scholar 

  136. Hodara R, Norris EH, Giasson BI, Mishizen-Eberz AJ, Lynch DR, Lee VM et al (2004) Functional consequences of alpha-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. J Biol Chem 279(46):47746–47753. PMID: 15364911

    Article  CAS  PubMed  Google Scholar 

  137. Schneeberger A, Tierney L, Mandler M (2015) Active immunization therapies for Parkinson's disease and multiple system atrophy. Mov Disord 11. PMID: 26260853

    Google Scholar 

  138. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14(5):501–503. PMID: 18391963

    Article  CAS  PubMed  Google Scholar 

  139. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 14(5):504–506. PMID: 18391962

    Article  CAS  PubMed  Google Scholar 

  140. Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ et al (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953. PMID: 23161999. PMCID: 3552321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lee HJ, Patel S, Lee SJ (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25(25):6016–6024. PMID: 15976091

    Article  CAS  PubMed  Google Scholar 

  142. Lee HJ, Bae EJ, Lee SJ (2014) Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases. Nat Rev Neurol 10(2):92–98. PMID: 24468877

    Article  CAS  PubMed  Google Scholar 

  143. Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ (2008) Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 40(9):1835–1849. PMID: 18291704

    Article  CAS  PubMed  Google Scholar 

  144. El-Agnaf OM, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ et al (2003) Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J 17(13):1945–1947. PMID: 14519670

    CAS  PubMed  Google Scholar 

  145. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L et al (2008) Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5(2):55–59. PMID: 18182779

    Article  CAS  PubMed  Google Scholar 

  146. Mollenhauer B, Trautmann E, Otte B, Ng J, Spreer A, Lange P et al (2012) alpha-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system. J Neural Transm 119(7):739–746. PMID: 22426833. PMCID: 3378837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Jenner P, Olanow CW (1998) Understanding cell death in Parkinson's disease. Ann Neurol 44(3 Suppl 1):S72–S84. PMID: 9749577

    Article  CAS  PubMed  Google Scholar 

  148. Mann VM, Cooper JM, Daniel SE, Srai K, Jenner P, Marsden CD et al (1994) Complex I, iron, and ferritin in Parkinson's disease substantia nigra. Ann Neurol 36(6):876–881. PMID: 7998774

    Article  CAS  PubMed  Google Scholar 

  149. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38(5):515–517. PMID: 16604074

    Article  CAS  PubMed  Google Scholar 

  150. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38(5):518–520. PMID: 16604072

    Article  CAS  PubMed  Google Scholar 

  151. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML et al (2010) PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med 2(52):52ra73. PMID: 20926834. PMCID: 3129986

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Moon HE, Paek SH (2015) Mitochondrial dysfunction in Parkinson's disease. Exp Neurobiol 24(2):103–116. PMID: 26113789. PMCID: 4479806

    Article  PubMed  PubMed Central  Google Scholar 

  153. Luo Y, Hoffer A, Hoffer B, Qi X (2015) Mitochondria: a therapeutic target for Parkinson's disease? Int J Mol Sci 16(9):20704–20730. PMID: 26340618. PMCID: 4613227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wang X, Yan MH, Fujioka H, Liu J, Wilson-Delfosse A, Chen SG et al (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 21(9):1931–1944. PMID: 22228096. PMCID: 3315202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Stichel CC, Zhu XR, Bader V, Linnartz B, Schmidt S, Lubbert H (2007) Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. Hum Mol Genet 16(20):2377–2393. PMID: 17412759

    Article  CAS  PubMed  Google Scholar 

  156. Niu J, Yu M, Wang C, Xu Z (2012) Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem 122(3):650–658. PMID: 22639965

    Article  CAS  PubMed  Google Scholar 

  157. Su YC, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 22(22):4545–4561. PMID: 23813973

    Article  CAS  PubMed  Google Scholar 

  158. Lemasters JJ (2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8(1):3–5. PMID: 15798367

    Article  CAS  PubMed  Google Scholar 

  159. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14. PMID: 21179058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A et al (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20(1):40–50. PMID: 20940149. PMCID: 3000675

    Article  CAS  PubMed  Google Scholar 

  161. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 28:57–87. PMID: 16022590

    Article  CAS  PubMed  Google Scholar 

  162. McNaught KS, Olanow CW (2006) Protein aggregation in the pathogenesis of familial and sporadic Parkinson's disease. Neurobiol Aging 27(4):530–545. PMID: 16207501

    Article  CAS  PubMed  Google Scholar 

  163. Moore DJ, Dawson VL, Dawson TM (2003) Role for the ubiquitin-proteasome system in Parkinson's disease and other neurodegenerative brain amyloidoses. Neuromolecular Med 4(1-2):95–108. PMID: 14528055

    Article  PubMed  Google Scholar 

  164. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278(27):25009–25013. PMID: 12719433

    Article  CAS  PubMed  Google Scholar 

  165. Rott R, Szargel R, Haskin J, Bandopadhyay R, Lees AJ, Shani V et al (2011) alpha-Synuclein fate is determined by USP9X-regulated monoubiquitination. Proc Natl Acad Sci U S A 108(46):18666–18671. PMID: 22065755. PMCID: 3219120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. von Coelln R, Dawson VL, Dawson TM (2004) Parkin-associated Parkinson's disease. Cell Tissue Res 318(1):175–184. PMID: 15503153

    Article  CAS  Google Scholar 

  167. Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (2006) The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol, PMID: 16403519 356(4):1036–1048

    Google Scholar 

  168. Manzoni C, Lewis PA (2013) Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies. FASEB J 27(9):3424–3429. PMID: 23682122. PMCID: 4194632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35(3):385–398. PMID: 19505575

    Article  CAS  PubMed  Google Scholar 

  170. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA et al (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67(12):1464–1472. PMID: 20697033

    Article  PubMed  Google Scholar 

  171. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA et al (2010) alpha-Synuclein impairs macroautophagy: implications for Parkinson's disease. J Cell Biol 190(6):1023–1037. PMID: 20855506. PMCID: 3101586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688):1292–1295. PMID: 15333840

    Article  CAS  PubMed  Google Scholar 

  173. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329(5999):1663–1667. PMID: 20798282. PMCID: 3235365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A et al (2014) Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain J Neurol 137(Pt 5):1481–1495. PMID: 24574503. PMCID: 3999713

    Article  Google Scholar 

  175. Herrero MT, Estrada C, Maatouk L, Vyas S (2015) Inflammation in Parkinson's disease: role of glucocorticoids. Front Neuroanat 9:32. PMID: 25883554. PMCID: 4382972

    Article  PubMed  PubMed Central  Google Scholar 

  176. Dzamko N, Geczy CL, Halliday GM (2015) Inflammation is genetically implicated in Parkinson's disease. Neuroscience 302:89–102. PMID: 25450953

    Article  CAS  PubMed  Google Scholar 

  177. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 26(1):6–17. PMID: 21322014

    Article  PubMed  Google Scholar 

  178. Kanaan NM, Kordower JH, Collier TJ (2008) Age and region-specific responses of microglia, but not astrocytes, suggest a role in selective vulnerability of dopamine neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in monkeys. Glia 56(11):1199–1214. PMID: 18484101. PMCID: 3388430

    Article  PubMed  PubMed Central  Google Scholar 

  179. Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S et al (2013) In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson's disease. Parkinsonism Relat Disord 19(1):47–52. PMID: 22841687

    Article  CAS  PubMed  Google Scholar 

  180. Alvarez-Erviti L, Couch Y, Richardson J, Cooper JM, Wood MJ (2011) Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci Res 69(4):337–342. PMID: 21255620

    Article  CAS  PubMed  Google Scholar 

  181. Chesselet MF, Richter F, Zhu C, Magen I, Watson MB, Subramaniam SR (2012) A progressive mouse model of Parkinson's disease: the Thy1-aSyn ("Line 61") mice. Neurotherapeutics 9(2):297–314. PMID: 22350713. PMCID: 3337020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V et al (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3(1):e1376. PMID: 18167537. PMCID: 2147051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Schildknecht S, Gerding HR, Karreman C, Drescher M, Lashuel HA, Outeiro TF et al (2013) Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. J Neurochem 125(4):491–511. PMID: 23452040

    Article  CAS  PubMed  Google Scholar 

  184. Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjorn M, Kuss M et al (2015) Lack of neuronal IFN-beta-IFNAR causes Lewy body- and Parkinson's disease-like dementia. Cell 163(2):324–339. PMID: 26451483. PMCID: 4601085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Russo I, Bubacco L, Greggio E (2014) LRRK2 and neuroinflammation: partners in crime in Parkinson's disease? J Neuroinflammation 11:52. PMID: 24655756. PMCID: 3994422

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12(11):1063–1070. PMID: 21983832. PMCID: 4140245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Dzamko N, Inesta-Vaquera F, Zhang J, Xie C, Cai H, Arthur S et al (2012) The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS One 7(6):e39132. PMID: 22723946. PMCID: 3377608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Gillardon F, Schmid R, Draheim H (2012) Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208:41–48. PMID: 22342962

    Article  CAS  PubMed  Google Scholar 

  189. Frank-Cannon TC, Tran T, Ruhn KA, Martinez TN, Hong J, Marvin M et al (2008) Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci 28(43):10825–10834. PMID: 18945890. PMCID: 2603252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Tran TA, Kallakury BV, Ambros RA, Ross JS (1998) Prognostic significance of tumor necrosis factors and their receptors in nonsmall cell lung carcinoma. Cancer 83(2):276–282. PMID: 9669810

    Article  CAS  PubMed  Google Scholar 

  191. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS et al (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501(7468):512–516. PMID: 24005326. PMCID: 3886920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Chopra R, Kalaiarasan P, Ali S, Srivastava AK, Aggarwal S, Garg VK, et al. PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population. BMJ Open 2014;4(2):e004239. PMID: 24578538. PMCID: 3939656.

    Google Scholar 

  193. Ellis GI, Zhi L, Akundi R, Bueler H, Marti F (2013) Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T-cell development and function. Eur J Immunol 43(12):3355–3360. PMID: 24037540. PMCID: 4539263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Akundi RS, Zhi L, Bueler H (2012) PINK1 enhances insulin-like growth factor-1-dependent Akt signaling and protection against apoptosis. Neurobiol Dis 45(1):469–478. PMID: 21945539. PMCID: 3225697

    Article  CAS  PubMed  Google Scholar 

  195. Waak J, Weber SS, Waldenmaier A, Gorner K, Alunni-Fabbroni M, Schell H et al (2009) Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1. FASEB J 23(8):2478–2489. PMID: 19276172

    Article  CAS  PubMed  Google Scholar 

  196. Trudler D, Weinreb O, Mandel SA, Youdim MB, Frenkel D (2014) DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J Neurochem 129(3):434–447. PMID: 24355073

    Article  CAS  PubMed  Google Scholar 

  197. Kumaran R, Vandrovcova J, Luk C, Sharma S, Renton A, Wood NW et al (2009) Differential DJ-1 gene expression in Parkinson's disease. Neurobiol Dis 36(2):393–400. PMID: 19716892

    Article  CAS  PubMed  Google Scholar 

  198. Chesselet MF, Richter F (2011) Modelling of Parkinson's disease in mice. Lancet Neurol 10(12):1108–1118. PMID: 22094131

    Article  PubMed  Google Scholar 

  199. Torrent R, De Angelis RF, Dell'Era P, Memo M, Raya A, Consiglio A (2015) Using iPS cells toward the understanding of Parkinson's disease. J Clin Med 4(4):548–566. PMID: 26239346. PMCID: 4470155

    Article  PubMed  PubMed Central  Google Scholar 

  200. Beevers JE, Caffrey TM, Wade-Martins R (2013) Induced pluripotent stem cell (iPSC)-derived dopaminergic models of Parkinson's disease. Biochem Soc Trans 41(6):1503–1508. PMID: 24256244

    Article  CAS  PubMed  Google Scholar 

  201. Pahwa R, Lyons KE (2014) Treatment of early Parkinson's disease. Curr Opin Neurol 27(4):442–449. PMID: 24950010

    Article  CAS  PubMed  Google Scholar 

  202. Watts RL, Lyons KE, Pahwa R, Sethi K, Stern M, Hauser RA et al (2010) Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease. Mov Disord 25(7):858–866. PMID: 20461803

    Article  PubMed  Google Scholar 

  203. Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E et al (2014) The modern pre-levodopa era of Parkinson's disease: insights into motor complications from sub-Saharan Africa. Brain J Neurol 137(Pt 10):2731–2742. PMID: 25034897. PMCID: 4163032

    Article  Google Scholar 

  204. Giugni JC, Okun MS (2014) Treatment of advanced Parkinson's disease. Curr Opin Neurol 27(4):450–460. PMID: 24978634. PMCID: 4140171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Fox SH, Katzenschlager R, Lim SY, Ravina B, Seppi K, Coelho M et al (2011) The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinson's disease. Mov Disord 26(Suppl 3):S2–41. PMID: 22021173

    Article  PubMed  Google Scholar 

  206. Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 20(2):190–199. PMID: 15551331

    Article  PubMed  Google Scholar 

  207. Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M et al (2013) Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 12(4):346–356. PMID: 23485610

    Article  CAS  PubMed  Google Scholar 

  208. LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P et al (2008) Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 63(3):295–302. PMID: 18306243

    Article  CAS  PubMed  Google Scholar 

  209. Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P et al (2008) A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 70(23):2233–2240. PMID: 18519872

    Article  CAS  PubMed  Google Scholar 

  210. Tomlinson CL, Patel S, Meek C, Herd CP, Clarke CE, Stowe R, et al. (2013) Physiotherapy versus placebo or no intervention in Parkinson's disease. Cochrane Database Syst Rev. ;9:CD002817. PMID: 24018704.

    Google Scholar 

  211. Li F, Harmer P, Fitzgerald K, Eckstrom E, Stock R, Galver J et al (2012) Tai chi and postural stability in patients with Parkinson's disease. N Engl J Med 366(6):511–519. PMID: 22316445. PMCID: 3285459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Barker RA, Studer L, Cattaneo E, Takahashi J (2015) G-force PD: a global initiative in coordinating stem-cell based dopamine treatments for Parkinson's disease. NPJ Parkinsons Dis 1

    Google Scholar 

  213. Worth PJ (2013) When the going gets tough: how to select patients with Parkinson’s disease for advanced therapies. Pract Neurol 13:140–152

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

AN is funded by a Career Development Award from Parkinson’s UK; RB is funded by the Reta Lila Weston Institute of Neurological Studies. This work was supported in part by the Wellcome Trust/MRC joint call in Neurodegeneration award (WT089698) to the UK Parkinson’s disease Consortium (UKPDC) whose members are from the UCL Institute of Neurology, University of Sheffield and the MRC protein phosphorylation unit Dundee.

Author information

Authors and Affiliations

  1. Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, 1, Wakefield Street, London, WC1N 1PJ, UK

    Alastair Noyce Ph.D., M.R.C.P. & Rina Bandopadhyay Ph.D.

Authors
  1. Alastair Noyce Ph.D., M.R.C.P.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rina Bandopadhyay Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rina Bandopadhyay Ph.D. .

Editor information

Editors and Affiliations

  1. University of Melbourne Florey Institute of Neuroscience and Mental Health, Parkville, Australia

    Philip Beart

  2. Pediatrics and Pharmacology Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael Robinson

  3. School of Life Sciences Bradford School of Pharmacy, University of Bradford, Bradford, United Kingdom

    Marcus Rattray

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J. Maragakis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Noyce, A., Bandopadhyay, R. (2017). Parkinson’s Disease: Basic Pathomechanisms and a Clinical Overview. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_3

Download citation

Publish with us

Policies and ethics

Search

Navigation