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Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson’s Disease: Insights into Mechanisms and Pathological Consequences

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Abstract 

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemic conditions. A higher risk of developing Parkinson’s disease (PD) in patients with T2DM has become evident in recent years. However, the molecular mechanisms underlying the interplay between T2DM and PD pathogenesis remain unknown. Nevertheless, emerging epidemiological studies have demonstrated many common molecular pathways that play an essential role in regulating normal cellular functioning are independently implicated in the progression and etiopathogenesis of T2DM and PD. This review summarizes some common shared pathophysiological mechanisms, including insulin resistance, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), autophagy, and the ubiquitin–proteasome system (UPS) that independently mediate the onset and etiopathogenesis of T2DM and PD. In this review, we summarize the studies that have reported the relationship between T2DM and PD. This review will provide insights into the common involvement of molecular pathways that may provide alternative treatment strategies for both T2DM and PD.

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Data Availability

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Abbreviations

6-OHDA:

6 Hydroxy dopamine

ABA:

Abscisic acid

AIM2 inflammasome:

Absent in melanoma 2 inflammasome

AKT:

Protein kinase B

AMP:

Adenosine monophosphate

AMPK:

Adenosine monophosphate-activated protein kinase

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

Atg:

Autophagy related

BBB:

Blood-brain barrier

Bcl-2:

B cell lymphoma 2

BDNF:

Brain-derived neurotrophic factor

BiP:

Immunoglobulin heavy chain binding protein

cAMP:

Cyclic AMP

CAT:

Catalase

CHOP:

C/EBP homologous protein

CMA:

Chaperone-mediated autophagy

COX-2:

Cyclooxygenase-2

CREB:

CAMP response element binding protein

CSF:

Cerebrospinal fluid

DA:

Dopamine

DA-ergic:

Dopaminergic

DAMP:

Damaged-associated molecular pattern

DJ-1:

DnaJ-1

DM:

Diabetes mellitus

Drp1:

Dynamin-related protein-1

EIF2AK3:

Eukaryotic translation initiation factor 2 alpha kinase 3

eIF2α:

Eukaryotic initiation factor 2 alpha

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinases ERK1

ETC:

Electron transport chain

Fis1:

Fission 1

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide–l

GLP-1R:

GLP-1 receptor

GLUT4:

Glucose transporters type 4

GPCR:

G protein-coupled receptor

Grp78 protein:

Glucose-regulated protein 78

GSK3-β:

Glycogen synthase kinase-3beta

hA:

Human amylin

HFD:

High-fat diet

h-IAPP:

Human islet amyloid polypeptide

Hrd1:

HMG–CoA reductase degradation protein-1

IAPP:

Islet amyloid polypeptide

Iba-1:

Ionized calcium binding adaptor molecule 1

IFN-γ:

Interferon gamma

IkBα:

NF-kappa-B inhibitor alpha (I-kappa-B-alpha) (IkB-alpha)

IKK-β:

Inhibitor of nuclear factor-kappaB (IkappaB) kinase beta

IL:

Interleukin

IL-18R α/β:

IL-18 receptor α/β

iNOS:

Inducible nitric oxide synthase

IPD:

Idiopathic PD

IPL:

Inferior parietal lobule

IRE1α:

Inositol requiring enzyme 1 α

IRN:

Isorhynchophylline

IRS:

Insulin receptor substrate

LAMP1:

Lysosomal-associated membrane protein type 1

LB:

Lewy body

LC3:

Microtubule-associated protein 1A/1B-light chain 3

LC:

Locus coeruleus

L-DOPA:

Levodopa

LRRK2:

Leucine-rich repeat kinase 2

MafA:

Musculoaponeurotic fibrosarcoma oncogene family A

MAPK:

Mitogen-activated protein kinase

MFG:

Middle frontal gyrus

MFN:

Mitochondrial mitofusin

MHC:

Major histocompatibility complex

Miro 1:

Mitochondrial rho GTPase 1

MMP:

Mitochondrial membrane potential

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydrodropyridine

MSK1:

Mitogen and stress-activated kinase-1

mTOR:

Mechanistic target of rapamycin

NADH:

Nicotinamide adenine dinucleotide (NAD) + hydrogen (H)

NADPH-oxidase:

Nicotinamide adenine nucleotide phosphate oxidase

NF-ΚB:

Nuclear factor-κB

NLRP3 inflammasome:

NOD-, LRR-, and pyrin domain-containing 3 inflammasome

Nrf2:

Nuclear factor erythroid 2–related factor 2

P2X4R:

P2X purinoceptor 4

P2X7R:

P2X purinoceptor 7

Pael-R:

Parkin-associated endothelin receptor-like receptor

Park2:

Ub ligase Parkin

PARP:

Poly ADP-ribose polymerase

PD:

Parkinson’s disease

PERK:

Pancreatic ER kinase (PKR)–like ER kinase

PGC1-α:

Peroxisome proliferator-activated receptor gamma coactivator 1

PI3K:

Phosphatidylinositol 3-phosphate kinase

PINK1:

PTEN-induced putative phosphatase 1

PKA:

Protein kinase A

PKB:

Protein kinase B

PPARs:

Peroxisome proliferator-activated receptors

PQ:

Paraquat

PTEN:

Phosphatase and tensin homolog

Rab10:

Ras-related protein Rab 10

ROS:

Reactive oxygen species

SNCA:

Synuclein alpha

SNpc:

Substantia nigra pars compacta

SOCE:

Store-operated calcium entry (SOCE)

SOCS:

Suppressor of cytokine signaling

SOD:

Superoxide dismutase

STZ:

Streptozotocin

SUMO-1:

Substrate for ubiquitin-like modifier-1

T2DM:

Type 2 diabetes mellitus

TFB1M:

Transcription factor B1 mitochondrial

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

TOM20:

Translocase of the outer membrane 20

TRPC1:

Transient receptor potential channel 1

UCH-L1:

Ubiquitin carboxy-terminal hydrolase L1

UCP2:

Uncoupling protein 2

UPDRS:

Unified Parkinson Disease Rating Scale

UPR:

Unfolded protein response

UPS:

Ubiquitin proteasome system

VDAC:

Voltage-dependent anion-selective channel

WFS1:

Wolfram syndrome gene 1

XBP1:

X-box-binding protein 1

References

  1. Hong CT, Chen KY, Wang W, Chiu JY, Wu D, Chao TY, Hu CJ, Chau KD, Bamodu OA (2020) Insulin resistance promotes Parkinson’s disease through aberrant expression of α-synuclein, mitochondrial dysfunction, and deregulation of the polo-like kinase 2 signaling. Cells 9(3):740. https://doi.org/10.3390/cells9030740

    Article  CAS  PubMed Central  Google Scholar 

  2. Xuan WT, Wang H, Zhou P, Ye T, Gao HW, Ye S, Wang JH, Chen ML, Song H, Wang Y, Cai B (2020) Berberine ameliorates rats model of combined s disease and type diabetes mellitus via the suppression of endoplasmic reticulum stress. Biotech 10(8):359. https://doi.org/10.1007/s13205-020-02354-7

    Article  Google Scholar 

  3. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013

    Article  Google Scholar 

  4. Yang YW, Hsieh TF, Li CI, Liu CS, Lin WY, Chiang JH, Li TC, Lin CC (2017) Increased risk of Parkinson disease with diabetes mellitus in a population-based study. Medicine (Baltimore) 96(3):e5921. https://doi.org/10.1097/MD.0000000000005921

    Article  Google Scholar 

  5. Cereda E, Barichella M, Pedrolli C, Klersy C, Cassani E, Caccialanza R, Pezzoli G (2011) Diabetes and risk of Parkinson’s disease: a systematic review and meta-analysis. Diabetes Care 34(12):2614–2623. https://doi.org/10.2337/dc11-1584

    Article  PubMed  PubMed Central  Google Scholar 

  6. Santiago JA, Potashkin JA (2013) Shared dysregulated pathways lead to Parkinson’s disease and diabetes. Trends Mol Med 19(3):176–186. https://doi.org/10.1016/j.molmed.2013.01.002

    Article  CAS  PubMed  Google Scholar 

  7. Katila N, Bhurtel S, Shadfar S, Srivastav S, Neupane S, Ojha U, Jeong GS, Choi DY (2017) Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology 125:396–407. https://doi.org/10.1016/j.neuropharm.2017.08.015

    Article  CAS  PubMed  Google Scholar 

  8. Grieco M, Giorgi A, Gentile MC, d’Erme M, Morano S, Maras B, Filardi T (2019) Glucagon-like peptide-1: a focus on neurodegenerative diseases. Front Neurosci 18(13):1112. https://doi.org/10.3389/fnins.2019.01112

    Article  Google Scholar 

  9. Sandyk R (1993) The relationship between diabetes mellitus and Parkinson’s disease. Int J Neurosci 69(1–4):125–130. https://doi.org/10.3109/00207459309003322

    Article  CAS  PubMed  Google Scholar 

  10. Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N, Niccolini F, Politis M (2018) Diabetes mellitus and Parkinson disease. Neurology 8 90(19):1654–1662. https://doi.org/10.1212/WNL.0000000000005475

    Article  Google Scholar 

  11. XuQ PY, Huang X, Hollenbeck A, Blair A, Schatzkin A, Chen H (2011) Diabetes and risk of Parkinson’s disease. Diabetes Care 34(4):910–915. https://doi.org/10.2337/dc10-1922

    Article  Google Scholar 

  12. Qi L, Cornelis MC, Kraft P, Stanya KJ, Linda Kao WH, Pankow JS, Dupuis J, Florez JC, Fox CS, Paré G, Sun Q, Girman CJ, Laurie CC, Mirel DB, Manolio TA, Chasman DI, Boerwinkle E, Ridker PM, Hunter DJ, Meigs JB, Lee CH, Hu FB, van Dam RM (2010). Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC); Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19 (13):2706–15 https://doi.org/10.1093/hmg/ddq156

  13. Xiromerisiou G, Hadjigeorgiou GM, Papadimitriou A, Katsarogiannis E, Gourbali V, Singleton AB (2008) Association between AKT1 gene and Parkinson’s disease a protective haplotype. Neurosci Lett 436(2):232–4. https://doi.org/10.1016/j.neulet.2008.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jain D, Jain R, Eberhard D, Eglinger J, Bugliani M, Piemonti L, Marchetti P, Lammert E (2012) Age- and diet-dependent requirement of DJ-1 for glucose homeostasis in mice with implications for human type 2 diabetes. J Mol Cell Biol 4(4):221–230. https://doi.org/10.1093/jmcb/mjs025

    Article  CAS  PubMed  Google Scholar 

  15. Fukushima T, Tan X, Luo Y, Kanda H (2011) Serum vitamins and heavy metals in blood and urine, and the correlations among them in Parkinson’s disease patients in China. Neuroepidemiology 36(4):240–244. https://doi.org/10.1159/000328253

    Article  PubMed  Google Scholar 

  16. Yue X, Li H, Yan H, Zhang P, Chang L, Li T (2016) Risk of Parkinson disease in diabetes mellitus: an updated meta-analysis of population-based cohort studies. Medicine (Baltimore) 95(18):e3549. https://doi.org/10.1097/MD.0000000000003549

    Article  Google Scholar 

  17. Santos García D, Suárez Castro E, Expósito I, de Deus T, Tuñas C, Aneiros A, López Fernández M, Núñez Arias D, Bermúdez Torres M (2017) Comorbid conditions associated with Parkinson’s disease: a longitudinal and comparative study with Alzheimer disease and control subjects. J Neurol Sci 15(373):210–215. https://doi.org/10.1016/j.jns.2016.12.046

    Article  Google Scholar 

  18. Cheong JLY, de Pablo-Fernandez E, Foltynie T, Noyce AJ (2020) The association between type 2 diabetes mellitus and Parkinson’s disease. J Parkinsons Dis 10(3):775–789. https://doi.org/10.3233/JPD-191900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G (2012) Clinical features of Parkinson disease when onset of diabetes came first a case control study. Neurology 78(19):1507–11. https://doi.org/10.1212/WNL.0b013e3182553cc9

    Article  CAS  PubMed  Google Scholar 

  20. Bohnen NI, Kotagal V, Müller ML, Koeppe RA, Scott PJ, Albin RL, Frey KA, Petrou M (2014) Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease. Parkinsonism Relat Disord 20(12):1394–8. https://doi.org/10.1016/j.parkreldis.2014.10.008

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hölscher C (2020) Brain insulin resistance: role in neurodegenerative disease and potential for targeting. Expert Opin Investig Drugs 29(4):333–348. https://doi.org/10.1080/13543784.2020.1738383

    Article  CAS  PubMed  Google Scholar 

  22. Sirangelo I, Borriello M, Vilasi S, Iannuzzi C (2020) Hydroxytyrosol inhibits protein oligomerization and amyloid aggregation in human insulin. Int J Mol Sci 21(13):4636. https://doi.org/10.3390/ijms21134636

    Article  CAS  PubMed Central  Google Scholar 

  23. Cho JH, Kim JW, Shin JA, Shin J, Yoon KH (2011) β-cell mass in people with type 2 diabetes. J Diabetes Investig 2(1):6–17. https://doi.org/10.1111/j.2040-1124.2010.00072.x

    Article  CAS  PubMed  Google Scholar 

  24. Love KM, Liu J, Regensteiner JG, Reusch JEB, Liu Z (2020) GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes. J Diabetes 12(7):488–498. https://doi.org/10.1111/1753-0407.13045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mukherjee A, Morales-Scheihing D, Butler PC, Soto C (2015) Type 2 diabetes as a protein misfolding disease. Trends Mol Med 21(7):439–449. https://doi.org/10.1016/j.molmed.2015.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bosco D, Plastino M, Cristiano D, Colica C, Ermio C, De Bartolo M, Mungari P, Fonte G, Consoli D, Consoli A, Fava A (2012) Dementia is associated with insulin resistance in patients with Parkinson’s disease. J Neurol Sci 315(1–2):39–43. https://doi.org/10.1016/j.jns.2011.12.008

    Article  CAS  PubMed  Google Scholar 

  27. Ahmad MH, Fatima M, Mondal AC (2019) Role of hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis and insulin signaling in the pathophysiology of Alzheimer’s disease. Neuropsychobiology 77(4):197–205. https://doi.org/10.1159/000495521

    Article  CAS  PubMed  Google Scholar 

  28. Hong CT, Chen KY, Wang W, Chiu JY, Wu D, Chao TY, Hu CJ, Chau KD, Bamodu OA (2020) Insulin resistance promotes Parkinson’s disease through aberrant expression of α-synuclein, mitochondrial dysfunction, and deregulation of the polo-like kinase 2 signaling. Cells 9(3):740. https://doi.org/10.3390/cells9030740

    Article  CAS  PubMed Central  Google Scholar 

  29. Craft S, Watson GS (2004) Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 3(3):169–78. https://doi.org/10.1016/S1474-4422(04)00681-7

    Article  CAS  PubMed  Google Scholar 

  30. Sekar S, Taghibiglou C (2018) Elevated nuclear phosphatase and tensin homolog (PTEN) and altered insulin signaling in substantia nigral region of patients with Parkinson’s disease. Neurosci Lett 666:139–143. https://doi.org/10.1016/j.neulet.2017.12.049

    Article  CAS  PubMed  Google Scholar 

  31. Athauda D, Foltynie T (2016) Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol 145–146:98–120. https://doi.org/10.1016/j.pneurobio.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  32. Funk N, Munz M, Ott T, Brockmann K, Wenninger-Weinzierl A, Kühn R, Vogt-Weisenhorn D, Giesert F, Wurst W, Gasser T, Biskup S (2019) The Parkinson’s disease-linked leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4. Sci Rep 9(1):4515. https://doi.org/10.1038/s41598-019-40808-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang T, Yuan F, Chen Z, Zhu S, Chang Z, Yang W, Deng B, Que R, Cao P, Chao Y, Chan L, Pan Y, Wang Y, Xu L, Lyu Q, Chan P, Yenari MA, Tan EK, Wang Q. Vascular, inflammatory and metabolic risk factors in relation to dementia in Parkinson’s disease patients with type 2 diabetes mellitus. Aging (Albany NY) 12(15):15682–15704. https://doi.org/10.18632/aging.103776.

  34. Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, Yuan Q, Yu H, Xu W, Xie X (2019) New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol 20:247–260. https://doi.org/10.1016/j.redox.2018.09.025

    Article  CAS  PubMed  Google Scholar 

  35. Ahmad MH, Rizvi MA, Fatima M, Mondal AC (2021) Pathophysiological implications of neuroinflammation mediated HPA axis dysregulation in the prognosis of cancer and depression. Mol Cell Endocrinol 520:111093. https://doi.org/10.1016/j.mce.2020.111093

  36. Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP (2013) Diabetes mellitus and inflammation. Curr Diab Rep 13(3):435–444. https://doi.org/10.1007/s11892-013-0375-y

    Article  CAS  PubMed  Google Scholar 

  37. Subba R, Sandhir R, Singh SP, Mallick BN, Mondal AC (2021) Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control. Eur J Neurosci 53(8):2870–2900. https://doi.org/10.1111/ejn.15136

    Article  PubMed  Google Scholar 

  38. Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH (2017) A new treatment strategy for Parkinson’s disease through the gut-brain axis: the glucagon-like peptide-1 receptor pathway. Cell Transplant 26(9):1560–1571. https://doi.org/10.1177/0963689717721234

    Article  PubMed  PubMed Central  Google Scholar 

  39. Badawi A, Klip A, Haddad P, Cole DE, Bailo BG, El-Sohemy A, Karmali M (2010) Type 2 diabetes mellitus and inflammation: prospects for biomarkers of risk and nutritional intervention. Diabetes Metab Syndr Obes 3:173–186. https://doi.org/10.2147/dmsott.s9089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Conti P, Ronconi G, Kritas SK, Caraffa A, Theoharides TC (2018) Activated mast cells mediate low-grade inflammation in type 2 diabetes: interleukin-37 could be beneficial. Can J Diabetes 42(5):568–573. https://doi.org/10.1016/j.jcjd.2018.01.008

    Article  PubMed  Google Scholar 

  41. Cheng KT, Ong HL, Liu X, Ambudkar IS (2013) Contribution and regulation of TRPC channels in store-operated Ca2+ entry. Curr Top Membr 71:149–179. https://doi.org/10.1016/B978-0-12-407870-3.00007-X.PMID:23890115;

    Article  CAS  PubMed  Google Scholar 

  42. Wang J, Li Y, Lai K, Zhong Q, Demin KA, Kalueff AV, Song C (2020) High-glucose/high-cholesterol diet in zebrafish evokes diabetic and affective pathogenesis: the role of peripheral and central inflammation, microglia and apoptosis. Prog Neuropsychopharmacol Biol Psychiatry 96:109752. https://doi.org/10.1016/j.pnpbp.2019.109752

    Article  CAS  PubMed  Google Scholar 

  43. Wang D, Wang H, Gao H, Zhang H, Zhang H, Wang Q, Sun Z (2011) P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Biosci 10:28. https://doi.org/10.1186/s13578-020-00388-1

    Article  Google Scholar 

  44. Sun X, Han F, Yi J, Han L, Wang B (2011) Effect of aspirin on the expression of hepatocyte NF-κB and serum TNF-α in streptozotocin-induced type 2 diabetic rats. J Korean Med Sci. 26(6):765–70. https://doi.org/10.3346/jkms.2011.26.6.765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108(3):437–446. https://doi.org/10.1172/JCI11559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pajares M, Rojo IA, Manda G, Boscá L, Cuadrado A (2020) Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells 9(7):1687. https://doi.org/10.3390/cells9071687

    Article  CAS  PubMed Central  Google Scholar 

  47. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7(4):354–365. https://doi.org/10.1016/j.nurt.2010.05.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chatterjee K, Roy A, Banerjee R, Choudhury S, Mondal B, Halder S, Basu P, Shubham S, Dey S, Kumar H (2020) Inflammasome and α-synuclein in Parkinson’s disease: a cross-sectional study. J Neuroimmunol 338:577089. https://doi.org/10.1016/j.jneuroim.2019.577089

    Article  CAS  PubMed  Google Scholar 

  49. Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10(3):253–263. https://doi.org/10.1016/S1474-4422(11)70015-1

    Article  CAS  PubMed  Google Scholar 

  50. Rodríguez-Cruz A, Romo-Mancillas A, Mendiola-Precoma J, Escobar-Cabrera JE, García-Alcocer G, Berumen LC (2019) Effect of valerenic acid on neuroinflammation in a MPTP-induced mouse model of Parkinson’s disease. IBRO Rep 8:28–35. https://doi.org/10.1016/j.ibror.2019.12.002

    Article  PubMed  PubMed Central  Google Scholar 

  51. Chen H, O’Reilly EJ, Schwarzschild MA, Ascherio A (2008) Peripheral inflammatory biomarkers and risk of Parkinson’s disease. Am J Epidemiol 167(1):90–95. https://doi.org/10.1093/aje/kwm260

    Article  PubMed  Google Scholar 

  52. Lee S, Lee Y, Ha S, Chung HY, Kim H, Hur JS, Lee J (2020) Anti-inflammatory effects of usnic acid in an MPTP-induced mouse model of Parkinson’s disease. Brain Res 1730:146642. https://doi.org/10.1016/j.brainres.2019.146642

    Article  CAS  PubMed  Google Scholar 

  53. O’Neill E, Yssel JD, McNamara C, Harkin A (2020) Pharmacological targeting of β2-adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson’s disease. Br J Pharmacol 177(2):282–297. https://doi.org/10.1111/bph.14862

    Article  CAS  PubMed  Google Scholar 

  54. Las G, Oliveira MF, Shirihai OS (2020) Emerging roles of β-cell mitochondria in type-2-diabetes. Mol Aspects Med 71:100843. https://doi.org/10.1016/j.mam.2019.100843

    Article  CAS  PubMed  Google Scholar 

  55. Kajihara N, Kukidome D, Sada K, Motoshima H, Furukawa N, Matsumura T, Nishikawa T, Araki E (2017) Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells. J Diabetes Investig 8(6):750–761. https://doi.org/10.1111/jdi.12678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sharoyko VV, Abels M, Sun J, Nicholas LM, Mollet IG, Stamenkovic JA, Göhring I, Malmgren S, Storm P, Fadista J, Spégel P, Metodiev MD, Larsson NG, Eliasson L, Wierup N, Mulder H (2014) Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes. Hum Mol Genet 23(21):5733–5749. https://doi.org/10.1093/hmg/ddu288

    Article  CAS  PubMed  Google Scholar 

  57. Luo X, Li R, Yan LJ (2015) Roles of pyruvate, NADH, and mitochondrial complex I in redox balance and imbalance in β cell function and dysfunction. J Diabetes Res 2015:512618. https://doi.org/10.1155/2015/512618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson’s disease. J Neurochem 139(Suppl 1):216–231. https://doi.org/10.1111/jnc.13731

    Article  CAS  PubMed  Google Scholar 

  59. Park JS, Davis RL, Sue CM (2018) Mitochondrial dysfunction in Parkinson’s disease: new mechanistic insights and therapeutic perspectives. Curr Neurol Neurosci Rep 18(5):21. https://doi.org/10.1007/s11910-018-0829-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Filichia E, Hoffer B, Qi X, Luo Y (2016) Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci Rep 6:32656. https://doi.org/10.1038/srep32656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Valdinocci D, Simões RF, Kovarova J, Cunha-Oliveira T, Neuzil J, Pountney DL (2019) Intracellular and intercellular mitochondrial dynamics in Parkinson’s disease. Front Neurosci 13:930. https://doi.org/10.3389/fnins.2019.00930

    Article  PubMed  PubMed Central  Google Scholar 

  62. Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32. https://doi.org/10.1016/j.pneurobio.2013.04.004

    Article  CAS  PubMed  Google Scholar 

  63. Schapira AH (2007) Mitochondrial dysfunction in Parkinson’s disease. Cell Death Differ 14(7):1261–1266. https://doi.org/10.1038/sj.cdd.4402160

    Article  CAS  PubMed  Google Scholar 

  64. Lev N, Roncevic D, Ickowicz D, Melamed E, Offen D (2006) Role of DJ-1 in Parkinson’s disease. J Mol Neurosci 29(3):215–225. https://doi.org/10.1385/jmn:29:3:215

    Article  CAS  PubMed  Google Scholar 

  65. Martin I, Kim JW, Dawson VL, Dawson TM (2014) LRRK2 pathobiology in Parkinson’s disease. J Neurochem 131(5):554–565. https://doi.org/10.1111/jnc.12949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:120–131. https://doi.org/10.1111/j.1749-6632.2003.tb07470.x

    Article  CAS  PubMed  Google Scholar 

  67. Kones R (2010) Parkinson’s disease: mitochondrial molecular pathology, inflammation, statins, and therapeutic neuroprotective nutrition. Nutr Clin Pract 25(4):371–389. https://doi.org/10.1177/0884533610373932

    Article  PubMed  Google Scholar 

  68. Bae JH, Jo SI, Kim SJ, Lee JM, Jeong JH, Kang JS, Cho NJ, Kim SS, Lee EY, Moon JS (2019) Circulating cell-free mtDNA contributes to AIM2 inflammasome-mediated chronic inflammation in patients with type 2 diabetes. Cells 8(4):328. https://doi.org/10.3390/cells8040328

    Article  CAS  PubMed Central  Google Scholar 

  69. Rasheed M, Liang J, Wang C, Deng Y, Chen Z (2021) Epigenetic regulation of neuroinflammation in Parkinson’s disease. Int J Mol Sci 22(9):4956. https://doi.org/10.3390/ijms22094956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Naoi M, Maruyama W, Shamoto-Nagai M (2020) Rasagiline and selegiline modulate mitochondrial homeostasis, intervene apoptosis system and mitigate α-synuclein cytotoxicity in disease-modifying therapy for Parkinson’s disease. J Neural Transm (Vienna) 127(2):131–147. https://doi.org/10.1007/s00702-020-02150-w

    Article  CAS  Google Scholar 

  71. Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, Cass WA, Sullivan PG, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100(5):1375–1386. https://doi.org/10.1111/j.1471-4159.2006.04327.x

    Article  CAS  PubMed  Google Scholar 

  72. Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 150(8):963–976. https://doi.org/10.1038/sj.bjp.0707167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wu Y, Reece EA, Zhong J, Dong D, Shen WB, Harman CR, Yang P (2016) Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis. Am J Obstet Gynecol 215(3):366.e1-366.e10. https://doi.org/10.1016/j.ajog.2016.03.036

    Article  CAS  Google Scholar 

  74. Choi SK, Lim M, Yeon SI, Lee YH (2016) Inhibition of endoplasmic reticulum stress improves coronary artery function in type 2 diabetic mice. Exp Physiol 101(6):768–777. https://doi.org/10.1113/EP085508

    Article  CAS  PubMed  Google Scholar 

  75. Nomura J, Hosoi T, Kaneko M, Ozawa K, Nishi A, Nomura Y (2016) Neuroprotection by endoplasmic reticulum stress-induced HRD1 and chaperones: possible therapeutic targets for Alzheimer’s and Parkinson’s disease. Med Sci (Basel) 4(3):14. https://doi.org/10.3390/medsci4030014

    Article  CAS  Google Scholar 

  76. Fonseca SG, Gromada J, Urano F (2011) Endoplasmic reticulum stress and pancreatic β-cell death. Trends Endocrinol Metab 22(7):266–274. https://doi.org/10.1016/j.tem.2011.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hu Y, Liu J, Yuan Y, Chen J, Cheng S, Wang H, Xu Y (2018) Sodium butyrate mitigates type 2 diabetes by inhibiting PERK-CHOP pathway of endoplasmic reticulum stress. Environ Toxicol Pharmacol 64:112–121. https://doi.org/10.1016/j.etap.2018.09.002

    Article  CAS  PubMed  Google Scholar 

  78. Natrus LV, Osadchuk YS, Lisakovska OO, Labudzinskyi DO, Klys YG, Chaikovsky YB (2022) Effect of propionic acid on diabetes-induced impairment of unfolded protein response signaling and astrocyte/microglia crosstalk in rat ventromedial nucleus of the hypothalamus. Neural Plast 22(2022):6404964. https://doi.org/10.1155/2022/6404964

    Article  CAS  Google Scholar 

  79. Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29(1):42–61. https://doi.org/10.1210/er.2007-0015

    Article  CAS  PubMed  Google Scholar 

  80. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50(4):752–763. https://doi.org/10.1007/s00125-006-0590-z

    Article  CAS  PubMed  Google Scholar 

  81. Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M (2007) The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 50(12):2486–2494. https://doi.org/10.1007/s00125-007-0816-8

    Article  CAS  PubMed  Google Scholar 

  82. Farombi EO, Awogbindin IO, Olorunkalu PD, Ogbuewu E, Oyetunde BF, Agedah AE, Adeniyi PA (2020) Kolaviron protects against nigrostriatal degeneration and gut oxidative damage in a stereotaxic rotenone model of Parkinson’s disease. Psychopharmacology 237(11):3225–3236. https://doi.org/10.1007/s00213-020-05605-w

    Article  CAS  PubMed  Google Scholar 

  83. Li XM, Zhang XJ, Dong MX (2017) Isorhynchophylline attenuates MPP+-induced apoptosis through endoplasmic reticulum stress- and mitochondria-dependent pathways in PC12 cells: involvement of antioxidant activity. Neuromolecular Med 19(4):480–492. https://doi.org/10.1007/s12017-017-8462

    Article  CAS  PubMed  Google Scholar 

  84. Ning B, Zhang Q, Wang N, Deng M, Fang Y (2019) β-Asarone regulates ER stress and autophagy via inhibition of the PERK/CHOP/Bcl-2/Beclin-1 pathway in 6-OHDA-induced parkinsonian rats. Neurochem Res 44(5):1159–1166. https://doi.org/10.1007/s11064-019-02757-w

    Article  CAS  PubMed  Google Scholar 

  85. Gorbatyuk MS, Shabashvili A, Chen W, Meyers C, Sullivan LF, Salganik M, Lin JH, Lewin AS, Muzyczka N, Gorbatyuk OS (2012) Glucose regulated protein 78 diminishes α-synuclein neurotoxicity in a rat model of Parkinson disease. Mol Ther 20(7):1327–1337. https://doi.org/10.1038/mt.2012.28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Omura T, Kaneko M, Okuma Y, Orba Y, Nagashima K, Takahashi R, Fujitani N, Matsumura S, Hata A, Kubota K, Murahashi K, Uehara T, Nomura Y (2006) A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. J Neurochem 99(6):1456–1469. https://doi.org/10.1111/j.1471-4159.2006.04155.x

    Article  CAS  PubMed  Google Scholar 

  87. Tong Y, Mukhamejanova Z, Zheng Y, Wen T, Xu F, Pang J (2021) Marine-derived xyloketal compound ameliorates MPP+-induced neuronal injury through regulating of the IRE1/XBP1 signaling pathway. ACS Chem Neurosci 12(16):3101–3111. https://doi.org/10.1021/acschemneuro.1c00362

    Article  CAS  PubMed  Google Scholar 

  88. Valdés P, Mercado G, Vidal RL, Molina C, Parsons G, Court FA, Martinez A, Galleguillos D, Armentano D, Schneider BL, Hetz C (2014) Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci U S A 111(18):6804–6809. https://doi.org/10.1073/pnas.1321845111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sado M, Yamasaki Y, Iwanaga T, Onaka Y, Ibuki T, Nishihara S, Mizuguchi H, Momota H, Kishibuchi R, Hashimoto T, Wada D, Kitagawa H, Watanabe TK (2009) Protective effect against Parkinson’s disease-related insults through the activation of XBP1. Brain Res 1257:16–24. https://doi.org/10.1016/j.brainres.2008.11.104

    Article  CAS  PubMed  Google Scholar 

  90. Sun Y, Selvaraj S, Pandey S, Humphrey KM, Foster JD, Wu M, Watt JA, Singh BB, Ohm JE (2018) MPP+ decreases store-operated calcium entry and TRPC1 expression in mesenchymal stem cell derived dopaminergic neurons. Sci Rep 8(1):11715. https://doi.org/10.1038/s41598-018-29528-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang T, Li X, Yang D, Zhang H, Zhao P, Fu J, Yao B, Zhou Z (2015) ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo. Neurotoxicology 48:109–119. https://doi.org/10.1016/j.neuro.2015.02.007

    Article  CAS  PubMed  Google Scholar 

  92. Saha S, Panigrahi DP, Patil S, Bhutia SK (2018) Autophagy in health and disease: a comprehensive review. Biomed Pharmacother 104:485–495. https://doi.org/10.1016/j.biopha.2018.05.007

    Article  CAS  PubMed  Google Scholar 

  93. Rocha M, Apostolova N, Diaz-Rua R, Muntane J, Victor VM (2020) Mitochondria and T2D: role of autophagy, ER stress, and inflammasome. Trends Endocrinol Metab 31(10):725–741. https://doi.org/10.1016/j.tem.2020.03.004

    Article  CAS  PubMed  Google Scholar 

  94. Marasco MR, Linnemann AK (2018) β-Cell autophagy in diabetes pathogenesis. Endocrinology 159(5):2127–2141. https://doi.org/10.1210/en.2017-03273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cheng Y, Ren X, Hait WN, Yang JM (2013) Therapeutic targeting of autophagy in disease: biology and pharmacology. Pharmacol Rev 65(4):1162–1197. https://doi.org/10.1124/pr.112.007120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52(6):1083–1086. https://doi.org/10.1007/s00125-009-1347-2

    Article  CAS  PubMed  Google Scholar 

  97. Choi SK, Kwon Y, Byeon S, Lee YH (2020) Stimulation of autophagy improves vascular function in the mesenteric arteries of type 2 diabetic mice. Exp Physiol 105(1):192–200. https://doi.org/10.1113/EP087737

    Article  CAS  PubMed  Google Scholar 

  98. Quan W, Jung HS, Lee MS (2013) Role of autophagy in the progression from obesity to diabetes and in the control of energy balance. Arch Pharm Res 36(2):223–229. https://doi.org/10.1007/s12272-013-0024-7

    Article  CAS  PubMed  Google Scholar 

  99. Wang Y, He D, Ni C, Zhou H, Wu S, Xue Z, Zhou Z (2016) Vitamin D induces autophagy of pancreatic β-cells and enhances insulin secretion. Mol Med Rep 14(3):2644–2650. https://doi.org/10.3892/mmr.2016.5531

    Article  CAS  PubMed  Google Scholar 

  100. Olanow CW, Brundin P (2013) Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord 28(1):31–40. https://doi.org/10.1002/mds.25373

    Article  CAS  PubMed  Google Scholar 

  101. Stefanis L, Emmanouilidou E, Pantazopoulou M, Kirik D, Vekrellis K, Tofaris GK (2019) How is alpha-synuclein cleared from the cell? J Neurochem 150(5):577–590. https://doi.org/10.1111/jnc.14704

    Article  CAS  PubMed  Google Scholar 

  102. 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. https://doi.org/10.1126/science

    Article  CAS  PubMed  Google Scholar 

  103. Bang Y, Kim KS, Seol W, Choi HJ (2016) LRRK2 interferes with aggresome formation for autophagic clearance. Mol Cell Neurosci 75:71–80. https://doi.org/10.1016/j.mcn.2016.06.007

    Article  CAS  PubMed  Google Scholar 

  104. Yue Z, Yang XW (2013) Dangerous duet: LRRK2 and α-synuclein jam at CMA. Nat Neurosci 16(4):375–377. https://doi.org/10.1038/nn.3361

    Article  CAS  PubMed  Google Scholar 

  105. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147(4):893–906. https://doi.org/10.1016/j.cell.2011.10.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bozi LHM, Campos JC (2017) Targeting the ubiquitin proteasome system in diabetic cardiomyopathy. J Mol Cell Cardiol 109:61–63. https://doi.org/10.1016/j.yjmcc.2017.06.009

    Article  CAS  PubMed  Google Scholar 

  107. McKinnon C, De Snoo ML, Gondard E, Neudorfer C, Chau H, Ngana SG, O’Hara DM, Brotchie JM, Koprich JB, Lozano AM, Kalia LV, Kalia SK (2020) Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein. Acta Neuropathol Commun 8(1):17. https://doi.org/10.1186/s40478-020-0894-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kawaguchi M, Minami K, Nagashima K, Seino S (2006) Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion. J Biol Chem 281(19):13015–13020. https://doi.org/10.1074/jbc.M601228200

    Article  CAS  PubMed  Google Scholar 

  109. Costes S, Vandewalle B, Tourrel-Cuzin C, Broca C, Linck N, Bertrand G, Kerr-Conte J, Portha B, Pattou F, Bockaert J, Dalle S (2009) Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets. Diabetes 58(5):1105–1115. https://doi.org/10.2337/db08-0926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gao C, Huang W, Kanasaki K, Xu Y (2014) The role of ubiquitination and sumoylation in diabetic nephropathy. Biomed Res Int 2014:160692. https://doi.org/10.1155/2014/160692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Haataja L, Gurlo T, Huang CJ, Butler PC (2008) Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev 29(3):303–316. https://doi.org/10.1210/er.2007-0037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Costes S (2018) Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes. Curr Opin Pharmacol 43:104–110. https://doi.org/10.1016/j.coph.2018.08.016

    Article  CAS  PubMed  Google Scholar 

  113. Singh S, Trikha S, Sarkar A, Jeremic AM (2016) Proteasome regulates turnover of toxic human amylin in pancreatic cells. Biochem J 473(17):2655–2670. https://doi.org/10.1042/BCJ20160026

    Article  CAS  PubMed  Google Scholar 

  114. White MF (2002) IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283(3):E413–E422. https://doi.org/10.1152/ajpendo.00514.2001

    Article  CAS  PubMed  Google Scholar 

  115. Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277(44):42394–42398. https://doi.org/10.1074/jbc.C200444200

    Article  CAS  PubMed  Google Scholar 

  116. Kim SJ, DeStefano MA, Oh WJ, Wu CC, Vega-Cotto NM, Finlan M, Liu D, Su B, Jacinto E (2012) mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol Cell 48(6):875–887. https://doi.org/10.1016/j.molcel.2012.09.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pelzer C, Cabalzar K, Wolf A, Gonzalez M, Lenz G, Thome M (2013) The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nat Immunol 14(4):337–345. https://doi.org/10.1038/ni.2540

    Article  CAS  PubMed  Google Scholar 

  118. Joshi N, Raveendran A, Nagotu S (2020) Chaperones and proteostasis: role in Parkinson’s disease. Diseases 8(2):24. https://doi.org/10.3390/diseases8020024

    Article  CAS  PubMed Central  Google Scholar 

  119. Momtaz S, Memariani Z, El-Senduny FF, Sanadgol N, Golab F, Katebi M, Abdolghaffari AH, Farzaei MH, Abdollahi M (2020) Targeting ubiquitin-proteasome pathway by natural products: novel therapeutic strategy for treatment of neurodegenerative diseases. Front Physiol 28(11):361. https://doi.org/10.3389/fphys.2020.00361

    Article  Google Scholar 

  120. Spratt DE, Martinez-Torres RJ, Noh YJ, Mercier P, Manczyk N, Barber KR, Aguirre JD, Burchell L, Purkiss A, Walden H, Shaw GS (2013) A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease. Nat Commun 4:1983. https://doi.org/10.1038/ncomms2983

    Article  CAS  PubMed  Google Scholar 

  121. Giguère N, Pacelli C, Saumure C, Bourque MJ, Matheoud D, Levesque D, Slack RS, Park DS, Trudeau LÉ (2018) Comparative analysis of Parkinson’s disease-associated genes in mice reveals altered survival and bioenergetics of Parkin-deficient dopamine neurons. J Biol Chem 293(25):9580–9593. https://doi.org/10.1074/jbc.RA117.000499

    Article  PubMed  PubMed Central  Google Scholar 

  122. Kawahata I, Fukunaga K (2020) Degradation of tyrosine hydroxylase by the ubiquitin-proteasome system in the pathogenesis of Parkinson’s disease and dopa-responsive dystonia. Int J Mol Sci 21(11):3779. https://doi.org/10.3390/ijms21113779.PMID:32471089

    Article  CAS  PubMed Central  Google Scholar 

  123. Yun JH, Lee DH, Jeong HS, Kim HS, Ye SK, Cho CH (2021) STAT3 activation in microglia exacerbates hippocampal neuronal apoptosis in diabetic brains. J Cell Physiol 236(10):7058–7070. https://doi.org/10.1002/jcp.30373

    Article  CAS  PubMed  Google Scholar 

  124. Cunha RA, Agostinho PM (2010) Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 20(Suppl 1):S95-116. https://doi.org/10.3233/JAD-2010-1408

    Article  CAS  PubMed  Google Scholar 

  125. Sánchez-Sarasúa S, Moustafa S, García-Avilés Á, López-Climent MF, Gómez-Cadenas A, Olucha-Bordonau FE, Sánchez-Pérez AM (2016) The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation. Nutr Metab (Lond) 26(13):73. https://doi.org/10.1186/s12986-016-0137-3

    Article  CAS  Google Scholar 

  126. Infante-Garcia C, Jose Ramos-Rodriguez J, Marin-Zambrana Y, Teresa Fernandez-Ponce M, Casas L, Mantell C, Garcia-Alloza M (2017) Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model. Brain Pathol 27(4):499–507. https://doi.org/10.1111/bpa.12433

    Article  CAS  PubMed  Google Scholar 

  127. Zhang PA, Sun Q, Li YC, Weng RX, Wu R, Zhang HH, Xu GY (2020) Overexpression of purinergic P2X4 receptors in hippocampus rescues memory impairment in rats with type 2 diabetes. Neurosci Bull 36(7):719–732. https://doi.org/10.1007/s12264-020-00478-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Alzoubi KH, Mokhemer E, Abuirmeileh AN (2018) Beneficial effect of etazolate on depression-like behavior and learning, and memory impairment in a model of Parkinson’s disease. Behav Brain Res 17(350):109–115. https://doi.org/10.1016/j.bbr.2018.05.004

    Article  CAS  Google Scholar 

  129. Kawashima S, Shimizu Y, Ueki Y, Matsukawa N (2021) Impairment of the visuospatial working memory in the patients with Parkinson’s disease: an fMRI study. BMC Neurol 21(1):335. https://doi.org/10.1186/s12883-021-02366-7

    Article  PubMed  PubMed Central  Google Scholar 

  130. Souza MF, Medeiros KAAL, Lins LCRF, Bispo JMM, Gois AM, Freire MAM, Marchioro M, Santos JR (2020) Intracerebroventricular injection of deltamethrin increases locomotion activity and causes spatial working memory and dopaminergic pathway impairment in rats. Brain Res Bull 154:1–8. https://doi.org/10.1016/j.brainresbull.2019.10.002

    Article  CAS  PubMed  Google Scholar 

  131. Hanoğlu L, Ercan FB, Mantar N, Helvacı Yılmaz N, Sitrava S, Özer F, Yuluğ B (2019) Accelerated forgetting and verbal memory consolidation process in idiopathic nondement Parkinson’s disease. J Clin Neurosci 70:208–213. https://doi.org/10.1016/j.jocn.2019.08.012

    Article  PubMed  Google Scholar 

  132. Christopher L, Duff-Canning S, Koshimori Y, Segura B, Boileau I, Chen R, Lang AE, Houle S, Rusjan P, Strafella AP (2015) Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease. Ann Neurol 77(2):269–280. https://doi.org/10.1002/ana.24323

    Article  CAS  PubMed  Google Scholar 

  133. Guo Z, Ruan Z, Zhang D, Liu X, Hou L, Wang Q (2022) Rotenone impairs learning and memory in mice through microglia-mediated blood brain barrier disruption and neuronal apoptosis. Chemosphere 291(Pt 2):132982. https://doi.org/10.1016/j.chemosphere.2021.132982

    Article  CAS  PubMed  Google Scholar 

  134. Hou L, Sun F, Sun W, Zhang L, Wang Q (2019) Lesion of the locus coeruleus damages learning and memory performance in paraquat and maneb-induced mouse Parkinson’s disease model. Neuroscience 1(419):129–140. https://doi.org/10.1016/j.neuroscience.2019.09.006

    Article  CAS  Google Scholar 

  135. Wang SY, Wu SL, Chen TC, Chuang CS (2020) Antidiabetic agents for treatment of Parkinson’s disease: a meta-analysis. Int J Environ Res Public Health 17(13):4805. https://doi.org/10.3390/ijerph17134805

    Article  CAS  PubMed Central  Google Scholar 

  136. Ahmad MH, Fatima M, Ali M, Rizvi MA, Mondal AC (2021) Naringenin alleviates paraquat-induced dopaminergic neuronal loss in SH-SY5Y cells and a rat model of Parkinson's disease. Neuropharmacology 201:108831. https://doi.org/10.1016/j.neuropharm.2021.108831

  137. Mor DE, Sohrabi S, Kaletsky R, Keyes W, Tartici A, Kalia V, Miller GW, Murphy CT (2020) Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria. Proc Natl Acad Sci U S A 117(42):26438–26447. https://doi.org/10.1073/pnas.2009838117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ryu YK, Go J, Park HY, Choi YK, Seo YJ, Choi JH, Rhee M, Lee TG, Lee CH, Kim KS (2020) Metformin regulates astrocyte reactivity in Parkinson’s disease and normal aging. Neuropharmacology 15(175):108173. https://doi.org/10.1016/j.neuropharm.2020.108173

    Article  CAS  Google Scholar 

  139. Paudel YN, Angelopoulou E, Piperi C, Shaikh MF, Othman I (2020) Emerging neuroprotective effect of metformin in Parkinson’s disease: a molecular crosstalk. Pharmacol Res 152:104593. https://doi.org/10.1016/j.phrs.2019.104593

    Article  CAS  PubMed  Google Scholar 

  140. Li Y, Li L, Hölscher C (2016) Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev Neurosci 27(7):689–711. https://doi.org/10.1515/revneuro-2016-0018

    Article  CAS  PubMed  Google Scholar 

  141. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T (2013) Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest 123(6):2730–2736. https://doi.org/10.1172/JCI68295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hölscher C (2014) Drugs developed for treatment of diabetes show protective effects in Alzheimer’s and Parkinson’s diseases. Sheng Li Xue Bao 66(5):497–510

    PubMed  Google Scholar 

  143. Sekar S, Taghibiglou C (2018) Elevated nuclear phosphatase and tensin homolog (PTEN) and altered insulin signaling in substantia nigral region of patients with Parkinson’s disease. Neurosci Lett 14(666):139–143. https://doi.org/10.1016/j.neulet.2017.12.049

    Article  CAS  Google Scholar 

  144. Lopez Vicchi F, Luque GM, Brie B, Nogueira JP, Garcia Tornadu I, Becu-Villalobos D (2016) Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacol Res 109:74–80. https://doi.org/10.1016/j.phrs.2015.12.029

    Article  CAS  PubMed  Google Scholar 

  145. Chang YH, Yen SJ, Chang YH, Wu WJ, Lin KD (2021) Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus. Eur J Neurol 28(2):430–437. https://doi.org/10.1111/ene.14542

    Article  PubMed  Google Scholar 

  146. Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88(2):494–501. https://doi.org/10.1046/j.1471-4159.2003.02210.x

    Article  CAS  PubMed  Google Scholar 

  147. Struck LK, Rodnitzky RL, Dobson JK (1990) Stroke and its modification in Parkinson’s disease. Stroke 21(10):1395–1399. https://doi.org/10.1161/01.str.21.10.1395

    Article  CAS  PubMed  Google Scholar 

  148. Levine RL, Jones JC, Bee N (1992) Stroke and Parkinson’s disease. Stroke 23(6):839–42. https://doi.org/10.1161/01.str.23.6.839

    Article  CAS  PubMed  Google Scholar 

  149. Pressley JC, Louis ED, Tang MX, Cote L, Cohen PD, Glied S, Mayeux R (2003) The impact of comorbid disease and injuries on resource use and expenditures in parkinsonism. Neurology 14 60(1):87–93. https://doi.org/10.1212/wnl.60.1.87.24

    Article  CAS  Google Scholar 

  150. Guttman M, Slaughter PM, Theriault ME, DeBoer DP, Naylor CD (2004) Parkinsonism in Ontario: comorbidity associated with hospitalization in a large cohort. Mov Disord 19(1):49–53. https://doi.org/10.1002/mds.10648

    Article  PubMed  Google Scholar 

  151. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2006) Diabetes, smoking, and other medical conditions in relation to Parkinson’s disease risk. Parkinsonism Relat Disor 12(3):185–189. https://doi.org/10.1016/j.parkreldis.2005.09.004

    Article  Google Scholar 

  152. Leibson CL, Maraganore DM, Bower JH, Ransom JE, O’brien PC, Rocca WA, (2006) Comorbid conditions associated with Parkinson’s disease: a population-based study. Mov Disord 21(4):446–455. https://doi.org/10.1002/mds.20685

    Article  PubMed  Google Scholar 

  153. Scigliano G, Musicco M, Soliveri P, Piccolo I, Ronchetti G, Girotti F (2006) Reduced risk factors for vascular disorders in Parkinson disease patients: a case-control study. Stroke 37(5):1184–1188. https://doi.org/10.1161/01.STR.0000217384.03237.9c

    Article  PubMed  Google Scholar 

  154. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J (2007) Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 30(4):842–847. https://doi.org/10.2337/dc06-2011

    Article  PubMed  Google Scholar 

  155. Arvanitakis Z, Wilson RS, Bienias JL, Bennett DA (2007) Diabetes and parkinsonian signs in older persons. Alzheimer Dis Assoc Disord 21(2):144–149. https://doi.org/10.1097/WAD.0b013e31805ba768

    Article  PubMed  Google Scholar 

  156. Moran, L.B. and M.B.J.N. Graeber, Towards a pathway definition of Parkinson’s disease: a complex Moran LB, Graeber MB (2008). Towards a pathway definition of Parkinson’s disease: a complex disorder with links to cancer, diabetes and inflammation. Neurogenetics. 2008 Feb;9(1):1–13. https://doi.org/10.1007/s10048-007-0116-y.

  157. Driver JA, Smith A, Buring JE, Gaziano JM, Kurth T, Logroscino G (2008) Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 31(10):2003–2005. https://doi.org/10.2337/dc08-0688

    Article  PubMed  PubMed Central  Google Scholar 

  158. D’Amelio M, Ragonese P, Callari G, Di Benedetto N, Palmeri B, Terruso V, Salemi G, Famoso G, Aridon P, Savettieri G (2009) Diabetes preceding Parkinson’s disease onset. A case-control study Parkinsonism Relat Disord 15(9):660–664. https://doi.org/10.1016/j.parkreldis.2009.02.013

    Article  PubMed  Google Scholar 

  159. Menon R, Farina C (2011) Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes. PLoS ONE 6(4):e18660. https://doi.org/10.1371/journal.pone.0018660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Palacios N, Gao X, McCullough ML, Jacobs EJ, Patel AV, Mayo T, Schwarzschild MA, Ascherio A (2011) Obesity, diabetes, and risk of Parkinson’s disease. Mov Disord 26(12):2253–2259. https://doi.org/10.1002/mds.23855

    Article  PubMed  PubMed Central  Google Scholar 

  161. Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B (2011) Diabetes and the risk of developing Parkinson’s disease in Denmark. Diabetes Care. 34(5):1102–8. https://doi.org/10.2337/dc10-1333

    Article  PubMed  PubMed Central  Google Scholar 

  162. Sun Y, Chang YH, Chen HF, Su YH, Su HF, Li CY (2012) Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications. Diabetes Care 35(5):1047–1049. https://doi.org/10.2337/dc11-1511

    Article  PubMed  PubMed Central  Google Scholar 

  163. Wahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN (2012) Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord 18(6):753–758. https://doi.org/10.1016/j.parkreldis.2012.03.010

    Article  PubMed  Google Scholar 

  164. Santiago JA, Potashkin JA (2013) Integrative network analysis unveils convergent molecular pathways in Parkinson’s disease and diabetes. PLoS ONE 8(12):e83940. https://doi.org/10.1371/journal.pone.0083940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Santiago JA, Potashkin JA (2014). System-based approaches to decode the molecular links in Parkinson’s disease and diabetes. Neurobiol Dis 72 Pt A:84–91. https://doi.org/10.1016/j.nbd.2014.03.019.

  166. Kotagal V, Albin RL, Müller ML, Koeppe RA, Frey KA, Bohnen NI (2013) Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat Disord 19(5):522–526. https://doi.org/10.1016/j.parkreldis.2013.01.016

    Article  PubMed  PubMed Central  Google Scholar 

  167. De Pablo-Fernandez E, Goldacre R, Pakpoor J, Noyce AJ, Warner TT (2018) Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology 91(2):e139–e142. https://doi.org/10.1212/WNL.0000000000005771

    Article  PubMed  Google Scholar 

  168. Zhu Y, Pu J, Chen Y, Zhang B (2020) Decreased risk of Parkinson’s disease in diabetic patients with thiazolidinediones therapy: an exploratory meta-analysis. PLoS ONE 14(10):e0224236. https://doi.org/10.1371/journal.pone.0224236

    Article  CAS  Google Scholar 

  169. Jeong SM, Han K, Kim D, Rhee SY, Jang W, Shin DW (2020) Body mass index, diabetes, and the risk of Parkinson’s disease. Mov Disord 35(2):236–244. https://doi.org/10.1002/mds.27922

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the School of Life Sciences, JNU.

Funding

ACM highly acknowledges the financial supports from DBT (BT/PR32907/MED/122/227/2019), Ministry of Science and Technology (Govt. of India). Institutional umbrella grants like DBT-BUILDER-Level-III (BT/INF/22/SP45382/2022), and DST-FIST-II to School of Life Sciences, JNU, New Delhi. Mr. Sandeep acknowledges the financial support from CSIR Grant (09/263(1219)/2019-EMR-I. MHA acknowledges the financial support from ICMR-SRF (45/07/2019/MP/BMS).

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  1. Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, Delhi, India

    Sandeep XXXX, Mir Hilal Ahmad, Linchi Rani & Amal Chandra Mondal

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  1. Sandeep XXXX
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  2. Mir Hilal Ahmad
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ACM conceptualized, framed, and finally edited the manuscript; Sandeep, MHA, and LR wrote the manuscript.

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Correspondence to Amal Chandra Mondal.

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XXXX, S., Ahmad, M.H., Rani, L. et al. Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson’s Disease: Insights into Mechanisms and Pathological Consequences. Mol Neurobiol 59, 4466–4487 (2022). https://doi.org/10.1007/s12035-022-02867-7

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