Skip to main content

Dopaminergic Axons: Key Recitalists in Parkinson’s Disease

Abstract

Parkinson's disease (PD) is associated with dopamine depletion in the striatum owing to the selective and progressive loss of the nigrostriatal dopaminergic neurons, which results in motor dysfunction and secondary clinical manifestations. The dopamine level in the striatum is preserved because of the innervation of the substantia nigra (SN) dopaminergic neurons into it. Therefore, protection of the SN neurons is crucial for maintaining the dopamine level in the striatum and for ensuring the desired motor coordination. Several strategies have been devised to protect the degenerating dopaminergic neurons or to restore the dopamine levels for treating PD. Most of the methods focus exclusively on preventing cell body death in the neurons. Although advances have been made in understanding the disease, the search for disease-modifying drugs is an ongoing process. The present review describes the evidence from studies involving patients with PD as well as PD models that axon terminals are highly vulnerable to exogenous and endogenous insults and degenerate at the early stage of the disease. Impairment of mitochondrial dynamics, Ca2+ homeostasis, axonal transport, and loss of plasticity of axon terminals appear before the neuronal degeneration in PD. Furthermore, distortion of synaptic morphology and reduction of postsynaptic dendritic spines are the neuropathological hallmarks of early-stage disease. Thus, the review proposes a shift in focus from discerning the mechanism of neuronal cell body loss and targeting it to an entirely different approach of preventing axonal degeneration. The review also suggests appropriate strategies to prevent the loss of synaptic terminals, which could induce regrowth of the axon and its auxiliary fibers and might offer relief from the symptomatic features of PD.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Tritsch NX, Sabatini BL (2012) Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron 76(1):33–50. https://doi.org/10.1016/j.neuron.2012.09.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Ayano G (2016) Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat 2(2):120. https://doi.org/10.4172/2471-271x.1000120

    Article  Google Scholar 

  3. Tagliaferro P, Burke RE (2016) Retrograde axonal degeneration in Parkinson disease. J Parkinsons Dis 6(1):1–15. https://doi.org/10.3233/jpd-150769

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang J, Culp ML, Craver JG, Darley-Usmar V (2018) Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson’s disease. J Neurochem 144:691–709. https://doi.org/10.1111/jnc.14308

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. McCormack A, Keating DJ, Chegeni N, Colella A, Wang JJ, Chataway T (2019) Abundance of synaptic vesicle-related proteins in alpha-synuclein-containing protein inclusions suggests a targeted formation mechanism. Neurotox Res 35(4):883–897. https://doi.org/10.1007/s12640-019-00014-0

    CAS  Article  PubMed  Google Scholar 

  6. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ (2014) Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 112:24–49. https://doi.org/10.1016/j.pneurobio.2013.10.004

    CAS  Article  PubMed  Google Scholar 

  7. Malik BR, Maddison DC, Smith GA, Peters OM (2019) Autophagic and endo-lysosomal dysfunction in neurodegenerative disease. Mol Brain 12(1):100. https://doi.org/10.1186/s13041-019-0504-x

    Article  PubMed  PubMed Central  Google Scholar 

  8. Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285(19):3657–3668. https://doi.org/10.1111/febs.14607

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Voronkov DN, Salkov VN, Anufriev PL, Khudoerkov RM (2018) Lewy bodies in Parkinson’s disease: histological, immunohistochemical and interferometric examinations. Arkh Patol 80(4):9–13. https://doi.org/10.17116/patol20188049

    CAS  Article  PubMed  Google Scholar 

  10. Prots I, Grosch J, Brazdis RM, Simmnacher K, Veber V, Havlicek S, Hannappel C, Krach F, Krumbiegel M, Schütz O, Reis A, Wrasidlo W, Galasko DR, Groemer TW, Masliah E, Schlötzer-Schrehardt U, Xiang W, Winkler J, Winner B (2018) α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc Natl Acad Sci U S A 115(30):7813–7818. https://doi.org/10.1073/pnas.1713129115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Bolam JP, Pissadaki EK (2012) Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord 27(12):1478–1483. https://doi.org/10.1002/mds.25135

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Pacelli C, Giguère N, Bourque MJ, Lévesque M, Slack RS, Trudeau LÉ (2015) Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 25(18):2349–2360. https://doi.org/10.1016/j.cub.2015.07.050

    CAS  Article  PubMed  Google Scholar 

  13. Franco-Iborra S, Perier C (2015) Neurodegeneration: the size takes it all. Curr Biol 25(18):R797–R800. https://doi.org/10.1016/j.cub.2015.07.062

    CAS  Article  PubMed  Google Scholar 

  14. Mamelak M (2018) Parkinson’s disease, the dopaminergic neuron and gammahydroxybutyrate. Neurol Ther 7(1):5–11. https://doi.org/10.1007/s40120-018-0091-2

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Guo W, Stoklund Dittlau K, Van Den Bosch L (2020) Axonal transport defects and neurodegeneration: molecular mechanisms and therapeutic implications. Semin Cell Dev Biol 99:133–150. https://doi.org/10.1016/j.semcdb.2019.07.010

    CAS  Article  PubMed  Google Scholar 

  17. Scorziello A, Borzacchiello D, Sisalli MJ, Di Martino R, Morelli M, Feliciello A (2020) Mitochondrial homeostasis and signaling in Parkinson’s disease. Front Aging Neurosci 12:100. https://doi.org/10.3389/fnagi.2020.00100

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Vos M, Lauwers E, Verstreken P (2010) Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front Synaptic Neurosci 2:139. https://doi.org/10.3389/fnsyn.2010.00139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Ludtmann MHR, Abramov AY (2018) Mitochondrial calcium imbalance in Parkinson’s disease. Neurosci Lett 663:86–90. https://doi.org/10.1016/j.neulet.2017.08.044

    CAS  Article  PubMed  Google Scholar 

  20. Reeve AK, Grady JP, Cosgrave EM, Bennison E, Chen C, Hepplewhite PD, Morris CM (2018) Mitochondrial dysfunction within the synapses of substantia nigra neurons in Parkinson’s disease. NPJ Parkinsons Dis 4(1):1–10. https://doi.org/10.1038/s41531-018-0044-6

    Article  Google Scholar 

  21. Morais VA, Verstreken P, Roethig A, Smet J, Snellinx A, Vanbrabant M, Haddad D, Frezza C, Mandemakers W, Vogt-Weisenhorn D, Van Coster R, Wurst W, Scorrano L, De Strooper B (2009) Parkinson’s disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med 1(2):99–111. https://doi.org/10.1002/emmm.200900006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Dixit A, Srivastava G, Verma D, Mishra M, Singh PK, Prakash O (1832) Singh MP (2013) Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and Maneb and Paraquat mice models of Parkinson’s disease. Biochim Biophys Acta 8:1227–1240. https://doi.org/10.1016/j.bbadis.2013.03.019

    CAS  Article  Google Scholar 

  23. Chen Y, Sheng ZH (2013) Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J Cell Biol 202(2):351–364. https://doi.org/10.1083/jcb.201302040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Chen C, Turnbull DM, Reeve AK (2019) Mitochondrial dysfunction in Parkinson’s disease—cause or consequence? Biology (Basel) 8(2):38. https://doi.org/10.3390/biology8020038

    CAS  Article  Google Scholar 

  25. Agrawal S, Dixit A, Singh A, Tripathi P, Singh D, Patel DK, Singh MP (2015) Cyclosporine A and MnTMPyP alleviate α-synuclein expression and aggregation in cypermethrin-induced Parkinsonism. Mol Neurobiol 52(3):1619–1628. https://doi.org/10.1007/s12035-014-8954-8

    CAS  Article  PubMed  Google Scholar 

  26. ur Rasheed MS, Tripathi MK, Mishra AK, Shukla S, Singh MP, (2016) Resveratrol protects from toxin-induced parkinsonism: plethora of proofs hitherto petty translational value. Mol Neurobiol 53(5):2751–2760. https://doi.org/10.1007/s12035-015-9124-3

    CAS  Article  Google Scholar 

  27. Podlesniy P, Puigròs M, Serra N, Fernández-Santiago R, Ezquerra M, Tolosa E, Trullas R (2019) Accumulation of mitochondrial 7S DNA in idiopathic and LRRK2 associated Parkinson’s disease. EBioMedicine 48:554–567. https://doi.org/10.1016/j.ebiom.2019.09.015

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dossi G, Squarcina L, Rango M (2019) In vivo mitochondrial function in idiopathic and genetic Parkinson’s disease. Metabolites 10(1):19. https://doi.org/10.3390/metabo10010019

    CAS  Article  PubMed Central  Google Scholar 

  29. Bury AG, Pyle A, Elson JL, Greaves L, Morris CM, Hudson G, Pienaar IS (2017) Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease. Ann Neurol 82(6):1016–1021. https://doi.org/10.1002/ana.25099

    CAS  Article  PubMed  Google Scholar 

  30. Flønes IH, Fernandez-Vizarra E, Lykouri M, Brakedal B, Skeie GO, Miletic H, Lilleng PK, Alves G, Tysnes OB, Haugarvoll K, Dölle C, Zeviani M, Tzoulis C (2018) Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathol (Berl) 135(3):409–425. https://doi.org/10.1007/s00401-017-1794-7

    Article  Google Scholar 

  31. Dixit A, Mehta R, Singh AK (2019) Proteomics in human Parkinson’s disease: present scenario and future directions. Cell Mol Neurobiol 39(7):901–915. https://doi.org/10.1007/s10571-019-00700-9

    Article  PubMed  Google Scholar 

  32. Segura-Aguilar J, Paris I, Muñoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 129(6):898–915. https://doi.org/10.1111/jnc.12686

    CAS  Article  PubMed  Google Scholar 

  33. Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, Greggio E, Bisaglia M, Veronesi M, Girotto S, Dalla Serra M, Perego C, Casella L, Bubacco L (2017) DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. Sci Rep 7:40699. https://doi.org/10.1038/srep40699

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG (2019) Dopamine: functions, signaling, and association with neurological diseases. Cell Mol Neurobiol 39(1):31–59. https://doi.org/10.1007/s10571-018-0632-3

    Article  PubMed  Google Scholar 

  35. Nirenberg MJ, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM (1996) The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. J Neurosci 16(2):436–447. https://doi.org/10.1523/jneurosci.16-02-00436.1996

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Hersch SM, Yi H, Heilman CJ, Edwards RH, Levey AI (1997) Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra. J Comp Neurol 388(2):211–227. https://doi.org/10.1002/(sici)1096-9861(19971117)388:2%3c211::aid-cne3%3e3.0.co;2-4

    CAS  Article  PubMed  Google Scholar 

  37. Segura-Aguilar J, Paris I (2014) Mechanisms of dopamine oxidation and parkinson's disease. In: Handbook of neurotoxicity, vol 2, pp 865–883. Springer, New York. https://doi.org/10.1007/978-1-4614-5836-4_16

  38. German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE (2015) Regulation of the dopamine and vesicular monoamine transporters: pharmacological targets and implications for disease. Pharmacol Rev 67(4):1005–1024. https://doi.org/10.1124/pr.114.010397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Castagnoli N, Petzer JP, Steyn S, Castagnoli K, Chen JF, Schwarzschild MA, Van Der Schyf CJ (2003) Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists. Neurology 61(11 SUPPL. 6):S62-68. https://doi.org/10.1212/01.wnl.0000095215.97585.59

    CAS  Article  PubMed  Google Scholar 

  40. Segura-Aguilar J (2017) On the role of endogenous neurotoxins and neuroprotection in Parkinson’s disease. Neural Regen Res 12(6):897–901. https://doi.org/10.4103/1673-5374.208560

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Singh AK, Tiwari MN, Upadhyay G, Patel DK, Singh D, Prakash O, Singh MP (2012) Long term exposure to cypermethrin induces nigrostriatal dopaminergic neurodegeneration in adult rats: postnatal exposure enhances the susceptibility during adulthood. Neurobiol Aging 33(2):404–415. https://doi.org/10.1016/j.neurobiolaging.2010.02.018

    CAS  Article  PubMed  Google Scholar 

  42. Toulorge D, Schapira AHV, Hajj R (2016) Molecular changes in the postmortem parkinsonian brain. J Neurochem 139:27–58. https://doi.org/10.1111/jnc.13696

    CAS  Article  PubMed  Google Scholar 

  43. Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357(6357):1255–1261. https://doi.org/10.1126/science.aam9080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Chung CY, Koprich JB, Siddiqi H, Isacson O (2009) Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV α-synucleinopathy. J Neurosci 29(11):3365–3373. https://doi.org/10.1523/jneurosci.5427-08.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Pellegrini L, Wetzel A, Grannó S, Heaton G, Harvey K (2017) Back to the tubule: microtubule dynamics in Parkinson’s disease. Cell Mol Life Sci 74(3):409–434. https://doi.org/10.1007/s00018-016-2351-6

    CAS  Article  PubMed  Google Scholar 

  46. Cartelli D, Cappelletti G (2017) Microtubule destabilization paves the way to Parkinson’s disease. Mol Neurobiol 54:6762–6774. https://doi.org/10.1007/s12035-016-0188-5

    CAS  Article  PubMed  Google Scholar 

  47. Brady ST, Morfini GA (2017) Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases. Neurobiol Dis 105:273–282. https://doi.org/10.1016/j.nbd.2017.04.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Panchal K, Tiwari AK (2021) Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases. Mitochondrion 56:118–135. https://doi.org/10.1016/j.mito.2020.10.005

    CAS  Article  PubMed  Google Scholar 

  49. Chu Y, Morfini GA, Langhamer LB, He Y, Brady ST, Kordower JH (2012) Alterations in axonal transport motor proteins in sporadic and experimental Parkinson’s disease. Brain 135(7):2058–2073. https://doi.org/10.1093/brain/aws133

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, Halliday GM, Bartus RT (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136(8):2419–2431. https://doi.org/10.1093/brain/awt192

    Article  PubMed  PubMed Central  Google Scholar 

  51. Morfini GA, Burns M, Binder LI, Kanaan NM, Lapointe N, Bosco DA, Brown RH, Brown H, Tiwari A, Hayward L, Edgar J, Nave KA, Garberrn J, Atagi Y, Song Y, Pigino G, Brady ST (2009) Axonal transport defects in neurodegenerative diseases. J Neurosci 29(41):12776–12786. https://doi.org/10.1523/jneurosci.3463-09.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Morfini G, Pigino G, Opalach K, Serulle Y, Moreira JE, Sugimori M, Llinás RR, Brady ST (2007) 1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C. Proc Natl Acad Sci U S A 104(7):2442–2447. https://doi.org/10.1073/pnas.0611231104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Böhm KJ, Winner B (2013) α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288(30):21742–21754. https://doi.org/10.1074/jbc.M113.451815

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. da Cruz M-J (2019) Hyper-serotonergic state determines onset and progression of idiopathic Parkinson’s disease. Med Hypotheses 133:109399. https://doi.org/10.1016/j.mehy.2019.109399

    Article  Google Scholar 

  55. Flippo KH, Strack S (2017) Mitochondrial dynamics in neuronal injury, development and plasticity. J Cell Sci 130(4):671–681. https://doi.org/10.1242/jcs.171017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Whitworth AJ, Pallanck LJ (2017) PINK1/Parkin mitophagy and neurodegeneration—what do we really know in vivo? Curr Opin Genet Dev 44:47–53. https://doi.org/10.1016/j.gde.2017.01.016

    CAS  Article  PubMed  Google Scholar 

  57. Haddad D, Nakamura K (2015) Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Lett 589:3702–3713. https://doi.org/10.1016/j.febslet.2015.10.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Podlesniy P, Vilas D, Taylor P, Shaw LM, Tolosa E, Trullas R (2016) Mitochondrial DNA in CSF distinguishes LRRK2 from idiopathic Parkinson’s disease. Neurobiol Dis 94:10–17. https://doi.org/10.1016/j.nbd.2016.05.019

    CAS  Article  PubMed  Google Scholar 

  59. Winklhofer KF (1802) Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 1:29–44. https://doi.org/10.1016/j.bbadis.2009.08.013

    CAS  Article  Google Scholar 

  60. Lu X, Kim-Han JS, Harmon S, Sakiyama-Elbert SE, O’Malley KL (2014) The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons. Mol Neurodegener 9(1):17. https://doi.org/10.1186/1750-1326-9-17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Pozo Devoto VM, Falzone TL (2017) Mitochondrial dynamics in Parkinson’s disease: a role for α-synuclein? Dis Model Mech 10(9):1075–1087. https://doi.org/10.1242/dmm.026294

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Burke RE, O’Malley K (2013) Axon degeneration in Parkinson’s disease. Exp Neurol 246:72–83. https://doi.org/10.1016/j.expneurol.2012.01.011

    CAS  Article  PubMed  Google Scholar 

  63. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206(5):655–670. https://doi.org/10.1083/jcb.201401070

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Trancikova A, Tsika E, Moore DJ (2012) Mitochondrial dysfunction in genetic animal models of Parkinson’s disease. Antioxid Redox Signal 16(9):896–919. https://doi.org/10.1089/ars.2011.4200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Amorim IS, Graham LC, Carter RN, Morton NM, Hammachi F, Kunath T, Pennetta G, Carpanini SM, Manson JC, Lamont DJ, Wishart TM, Gillingwater TH (2017) Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology. J Cell Sci 130(2):325–331. https://doi.org/10.1242/jcs.194241

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Mallet N, Delgado L, Chazalon M, Miguelez C, Baufreton J (2019) Cellular and synaptic dysfunctions in Parkinson’s disease: stepping out of the striatum. Cells 8(9):1005. https://doi.org/10.3390/cells8091005

    CAS  Article  PubMed Central  Google Scholar 

  68. Fazio P, Svenningsson P, Cselényi Z, Halldin C, Farde L, Varrone A (2018) Nigrostriatal dopamine transporter availability in early Parkinson’s disease. Mov Disord 33(4):592–599. https://doi.org/10.1002/mds.27316

    CAS  Article  PubMed  Google Scholar 

  69. Matuskey D, Tinaz S, Wilcox KC, Naganawa M, Toyonaga T, Dias M, Henry S, Pittman B, Ropchan J, Nabulsi N, Suridjan I, Comley RA, Huang Y, Finnema SJ, Carson RE (2020) Synaptic changes in Parkinson disease assessed with in vivo imaging. Ann Neurol 87(3):329–338. https://doi.org/10.1002/ana.25682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Pienaar IS, Burn D, Morris C, Dexter D (2012) Synaptic protein alterations in Parkinson’s disease. Mol Neurobiol 45(1):126–143. https://doi.org/10.1007/s12035-011-8226-9

    CAS  Article  PubMed  Google Scholar 

  71. Burré J (2015) The synaptic function of α-synuclein. J Parkinsons Dis 5:699–713. https://doi.org/10.3233/jpd-150642

    Article  PubMed  PubMed Central  Google Scholar 

  72. Soukup SF, Vanhauwaert R, Verstreken P (2018) Parkinson’s disease: convergence on synaptic homeostasis. EMBO J 37(18):e98960. https://doi.org/10.15252/embj.201898960

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Pan PY, Zhu Y, Shen Y, Yue Z (2019) Crosstalk between presynaptic trafficking and autophagy in Parkinson’s disease. Neurobiol Dis 122(2017):64–71. https://doi.org/10.1016/j.nbd.2018.04.020

    CAS  Article  PubMed  Google Scholar 

  74. Shimojo M, Madara J, Pankow S, Liu X, Yates J, Südhof TC, Maximov A (2019) Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity. Genes Dev 33(5–6):365–376. https://doi.org/10.1101/gad.320077.118

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Bereczki E, Bogstedt A, Höglund K, Tsitsi P, Brodin L, Ballard C, Svenningsson P, Aarsland D (2017) Synaptic proteins in CSF relate to Parkinson’s disease stage markers. NPJ Parkinsons Dis 3(1):7. https://doi.org/10.1038/s41531-017-0008-2

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bridi JC, Hirth F (2018) Mechanisms of α-Synuclein induced synaptopathy in parkinson’s disease. Front Neurosci 12:80. https://doi.org/10.3389/fnins.2018.00080

    Article  PubMed  PubMed Central  Google Scholar 

  77. Phan JA, Stokholm K, Zareba-Paslawska J, Jakobsen S, Vang K, Gjedde A, Landau AM, Romero-Ramos M (2017) Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease. Sci Rep 7(1):6363. https://doi.org/10.1038/s41598-017-06724-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Visanji NP, Brooks PL, Hazrati LN, Lang AE (2014) The prion hypothesis in Parkinson’s disease: Braak to the future. Acta Neuropathol Commun 1:2. https://doi.org/10.1186/2051-5960-1-2

    Article  Google Scholar 

  79. Longhena F, Faustini G, Missale C, Pizzi M, Spano P, Bellucci A (2017) The Contribution of α-synuclein spreading to Parkinson’s disease synaptopathy. Neural Plas 2017:5012129. https://doi.org/10.1155/2017/5012129

    CAS  Article  Google Scholar 

  80. Ma J, Gao J, Wang J, Xie A (2019) Prion-like mechanisms in Parkinson’s disease. Front Neurosci 13:552. https://doi.org/10.3389/fnins.2019.00552

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gorenberg EL, Chandra SS (2017) The role of co-chaperones in synaptic proteostasis and neurodegenerative disease. Front Neurosci 11:248. https://doi.org/10.3389/fnins.2017.00248

    Article  PubMed  PubMed Central  Google Scholar 

  82. Catoni C, Calì T, Brini M (2019) Calcium, dopamine and neuronal calcium sensor 1: their contribution to Parkinson’s disease. Front Mol Neurosci 12:55. https://doi.org/10.3389/fnmol.2019.00055

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Surmeier DJ, Schumacker PT, Guzman JD, Ilijic E, Yang B, Zampese E (2017) Calcium and Parkinson’s disease. Biochem Biophys Res Commun 483(4):1013–1019. https://doi.org/10.1016/j.bbrc.2016.08.168

    CAS  Article  PubMed  Google Scholar 

  84. Benkert J, Hess S, Roy S, Beccano-Kelly D, Wiederspohn N, Duda J, Simons C, Patil K, Gaifullina A, Mannal N, Dragicevic E, Spaich D, Müller S, Nemeth J, Hollmann H, Deuter N, Mousba Y, Kubisch C, Poetschke C, Striessnig J, Pongs O, Schneider T, Wade-Martins R, Patel S, Parlato R, Frank T, Kloppenburg P, Liss B (2019) Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease. Nat Commun 10(1):5094. https://doi.org/10.1038/s41467-019-12834-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Zaichick SV, McGrath KM, Caraveo G (2017) The role of Ca2+ signaling in Parkinson’s disease. Dis Model Mech 10(5):519–535. https://doi.org/10.1242/dmm.028738

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Brimblecombe KR, Vietti-Michelina S, Platt NJ, Kastli R, Hnieno A, Gracie CJ, Cragg SJ (2019) Calbindin-D28K limits dopamine release in ventral but not dorsal striatum by regulating Ca2+ availability and dopamine transporter function. ACS Chem Neurosci 10(8):3419–3426. https://doi.org/10.1021/acschemneuro.9b00325

    CAS  Article  PubMed  Google Scholar 

  87. Leandrou E, Emmanouilidou E, Vekrellis K (2019) Voltage-gated calcium channels and α-synuclein: implications in Parkinson’s disease. Front Mol Neurosci 12:237. https://doi.org/10.3389/fnmol.2019.00237

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Verma A, Ravindranath V (2020) CaV1.3 L-type calcium channels increase the vulnerability of substantia nigra dopaminergic neurons in MPTP mouse model of Parkinson’s disease. Front Aging Neurosci 11:382. https://doi.org/10.3389/fnagi.2019.00382

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Surmeier DJ, Guzman JN, Sanchez-Padilla J, Schumacker PT (2011) The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson’s disease. Neuroscience 198:221–231. https://doi.org/10.1016/j.neuroscience.2011.08.045

    CAS  Article  PubMed  Google Scholar 

  90. Sgobio C, Sun L, Ding J, Herms J, Lovinger DM, Cai H (2019) Unbalanced calcium channel activity underlies selective vulnerability of nigrostriatal dopaminergic terminals in Parkinsonian mice. Sci Rep 9(1):4857. https://doi.org/10.1038/s41598-019-41091-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Hurley MJ, Brandon B, Gentleman SM, Dexter DT (2013) Parkinson’s disease is associated with altered expression of Ca V1 channels and calcium-binding proteins. Brain 136(7):2077–2097. https://doi.org/10.1093/brain/awt134

    Article  PubMed  Google Scholar 

  92. Betzer C, Jensen PH (2018) Reduced cytosolic calcium as an early decisive cellular state in Parkinson’s disease and synucleinopathies. Front Neurosci 12:819. https://doi.org/10.3389/fnins.2018.00819

    Article  PubMed  PubMed Central  Google Scholar 

  93. Angelova PR, Ludtmann MHR, Horrocks MH, Negoda A, Cremades N, Klenerman D, Dobson CM, Wood NW, Pavlov EV, Gandhi S, Abramov AY (2016) Ca2+ is a key factor in α-synuclein-induced neurotoxicity. J Cell Sci 129(9):1792–1801. https://doi.org/10.1242/jcs.180737

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Verma M, Wills Z, Chu CT (2018) Excitatory dendritic mitochondrial calcium toxicity: implications for Parkinson’s and other neurodegenerative diseases. Front Neurosci 12:523. https://doi.org/10.3389/fnins.2018.00523

    Article  PubMed  PubMed Central  Google Scholar 

  95. Barazzuol L, Giamogante F, Brini M, Calì T (2020) PINK1/Parkin mediated mitophagy, Ca2+ signalling, and ER-mitochondria contacts in Parkinson’s disease. Int J Mol Sci 21:1772. https://doi.org/10.3390/ijms21051772

    CAS  Article  PubMed Central  Google Scholar 

  96. Lim J, Yue Z (2015) Neuronal aggregates: formation, clearance, and spreading. Dev Cell 32(4):491–501. https://doi.org/10.1016/j.devcel.2015.02.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69(4):628–649. https://doi.org/10.1016/j.neuron.2011.02.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Siciliano CA, Calipari ES, Ferris MJ, Jones SR (2015) Adaptations of presynaptic dopamine terminals induced by psychostimulant self-administration. ACS Chem Neurosci 6(1):27–36. https://doi.org/10.1021/cn5002705

    CAS  Article  PubMed  Google Scholar 

  99. Yorgason JT, Calipari ES, Ferris MJ, Karkhanis AN, Fordahl SC, Weiner JL, Jones SR (2016) Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology 101:471–479. https://doi.org/10.1016/j.neuropharm.2015.10.025

    CAS  Article  PubMed  Google Scholar 

  100. Cheng HC, Ulane CM, Burke RE (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67(6):715–725. https://doi.org/10.1002/ana.21995

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hasbani DM, O’Malley KL (2006) WldS mice are protected against the Parkinsonian mimetic MPTP. Exp Neurol 202(1):93–99. https://doi.org/10.1016/j.expneurol.2006.05.017

    CAS  Article  PubMed  Google Scholar 

  102. Murdoch JD, Rostosky CM, Gowrisankaran S, Arora AS, Soukup SF, Vidal R, Capece V, Freytag S, Fischer A, Verstreken P, Bonn S, Raimundo N, Milosevic I (2016) Endophilin—a deficiency induces the Foxo3a-Fbxo32 network in the brain and causes dysregulation of autophagy and the ubiquitin-proteasome system. Cell Rep 17(4):1071–1086. https://doi.org/10.1016/j.celrep.2016.09.058

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Jin EJ, Kiral FR, Ozel MN, Burchardt LS, Osterland M, Epstein D, Wolfenberg H, Prohaska S, Hiesinger PR (2018) Live observation of two parallel membrane degradation pathways at axon terminals. Curr Biol 28 (7):1027–1038e1024. https://doi.org/10.1016/j.cub.2018.02.032

  104. Stavoe AKH, Holzbaur ELF (2019) Autophagy in neurons. Annu Rev Cell Dev Biol 35:477–500. https://doi.org/10.1146/annurev-cellbio-100818-125242

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Olgiati S, Thomas A, Quadri M, Breedveld GJ, Graafland J, Eussen H, Douben H, de Klein A, Onofrj M, Bonifati V (2015) Early-onset Parkinsonism caused by alpha-synuclein gene triplication: clinical and genetic findings in a novel family. Parkinsonism Relat Disord 21(8):981–986. https://doi.org/10.1016/j.parkreldis.2015.06.005

    Article  PubMed  Google Scholar 

  106. Lee S, Imai Y, Gehrke S, Liu S, Lu B (2012) The synaptic function of LRRK2. Biochem Soc Trans 40(5):1047–1051. https://doi.org/10.1042/bst20120113

    CAS  Article  PubMed  Google Scholar 

  107. Arranz AM, Delbroek L, van Kolen K, Guimarães MR, Mandemakers W, Daneels G, Matta S, Calafate S, Shaban H, Baatsen P, de Bock PJ, Gevaert K, Berghe PV, Verstreken P, de Strooper B, Moechars D (2015) LRRK2 functions in synaptic vesicle endocytosis through a kinase dependent mechanism. J Cell Sci 128(3):541–552. https://doi.org/10.1242/jcs.158196

    CAS  Article  PubMed  Google Scholar 

  108. Xiong Y, Dawson TM, Dawson VL (2017) Models of LRRK2-associated Parkinson’s disease. Adv Neurobiol 14:163–191. https://doi.org/10.1007/978-3-319-49969-7_9

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kuhlmann N, Milnerwood AJ (2020) A critical LRRK at the synapse? The neurobiological function and pathophysiological dysfunction of LRRK2. Front Mol Neurosci 13:153. https://doi.org/10.3389/fnmol.2020.00153

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Cao M, Milosevic I, Giovedi S, De Camilli P (2014) Upregulation of Parkin in endophilin mutant mice. J Neurosci 34(49):16544–16549. https://doi.org/10.1523/jneurosci.1710-14.2014

    Article  PubMed  PubMed Central  Google Scholar 

  111. Sassone J, Serratto GM, Valtorta F, Silani V, Passafaro M, Ciammola A (2017) The synaptic function of Parkin. Brain 140(9):2265–2272. https://doi.org/10.1093/brain/awx006

    Article  PubMed  Google Scholar 

  112. Lee W, Koh S, Hwang S, Kim SH (2018) Presynaptic dysfunction by familial factors in Parkinson disease. Int Neurourol J 22:S115–S121. https://doi.org/10.5213/inj.1836216.108

    Article  PubMed  PubMed Central  Google Scholar 

  113. Williams ET, Chen X, Moore DJ (2017) VPS35, the retromer complex and Parkinson’s disease. J Parkinsons Dis 7(2):219–233. https://doi.org/10.3233/jpd-161020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Rahman AA, Morrison BE (2019) Contributions of VPS35 mutations to Parkinson’s disease. Neuroscience 401:1–10. https://doi.org/10.1016/j.neuroscience.2019.01.006

    CAS  Article  PubMed  Google Scholar 

  115. Eleuteri S, Albanese A (2019) VPS35-based approach: a potential innovative treatment in Parkinson’s disease. Front Neurol 10:1272. https://doi.org/10.3389/fneur.2019.01272

    Article  PubMed  PubMed Central  Google Scholar 

  116. Stanic J, Mellone M, Napolitano F, Racca C, Zianni E, Minocci D, Ghiglieri V, Thiolat ML, Li Q, Longhi A, De Rosa A, Picconi B, Bezard E, Calabresi P, Di Luca M, Usiello A, Gardoni F (2017) Rabphilin 3A: a novel target for the treatment of levodopa-induced dyskinesias. Neurobiol Dis 108:54–64. https://doi.org/10.1016/j.nbd.2017.08.001

    CAS  Article  PubMed  Google Scholar 

  117. Shi MM, Shi CH, Xu YM (2017) Rab GTPases: the key players in the molecular pathway of Parkinson’s disease. Front Cell Neurosci 11:81. https://doi.org/10.3389/fncel.2017.00081

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Lunati A, Lesage S, Brice A (2018) The genetic landscape of Parkinson’s disease. Rev Neurol (Paris) 174(9):628–643. https://doi.org/10.1016/j.neurol.2018.08.004

    CAS  Article  Google Scholar 

  119. Singh PK, Muqit MMK (2020) Parkinson’s: a disease of aberrant vesicle trafficking. Annu Rev Cell Dev Biol 36:237–264. https://doi.org/10.1146/annurev-cellbio-100818-125512

    CAS  Article  PubMed  Google Scholar 

  120. Song L, He Y, Ou J, Zhao Y, Li R, Cheng J, Lin CH, Ho MS (2017) Auxilin underlies progressive locomotor deficits and dopaminergic neuron loss in a Drosophila model of Parkinson’s disease. Cell Rep 18(5):1132–1143. https://doi.org/10.1016/j.celrep.2017.01.005

    CAS  Article  PubMed  Google Scholar 

  121. Nguyen M, Krainc D (2018) LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease. Proc Natl Acad Sci U S A 115(21):5576–5581. https://doi.org/10.1073/pnas.1717590115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Roosen DA, Landeck N, Conti M, Smith N, Saez-Atienzar S, Ding J, Beilina A, Kumaran R, Kaganovich A, Du Hoffmann J (2019) Mutations in Auxilin cause parkinsonism via impaired clathrin-mediated trafficking at the Golgi apparatus and synapse. BioRxiv. https://doi.org/10.1101/830802

    Article  Google Scholar 

  123. Fasano D, Parisi S, Pierantoni GM, De Rosa A, Picillo M, Amodio G, Pellecchia MT, Barone P, Moltedo O, Bonifati V, De Michele G, Nitsch L, Remondelli P, Criscuolo C, Paladino S (2018) Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations. Cell Death Dis 9(3):1–15. https://doi.org/10.1038/s41419-018-0410-7

    CAS  Article  Google Scholar 

  124. Cao M, Park D, Wu Y, De Camilli P (2020) Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1. Proc Natl Acad Sci U S A 117(22):12428–12434. https://doi.org/10.1073/pnas.2004335117

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Nguyen M, Wong YC, Ysselstein D, Severino A, Krainc D (2019) Synaptic, mitochondrial, and lysosomal dysfunction in Parkinson’s disease. Trends Neurosci 42(2):140–149. https://doi.org/10.1016/j.tins.2018.11.001

    CAS  Article  PubMed  Google Scholar 

  126. Vidyadhara DJ, Lee JE, Chandra SS (2019) Role of the endolysosomal system in Parkinson’s disease. J Neurochem 150(5):487–506. https://doi.org/10.1111/jnc.14820

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Agliardi C, Guerini FR, Zanzottera M, Riboldazzi G, Zangaglia R, Sturchio A, Casali C, Di Lorenzo C, Minafra B, Nemni R, Clerici M (2019) SNAP25 gene polymorphisms protect against Parkinson’s disease and modulate disease severity in patients. Mol Neurobiol 56(6):4455–4463. https://doi.org/10.1007/s12035-018-1386-0

    CAS  Article  PubMed  Google Scholar 

  128. Longhena F, Faustini G, Varanita T, Zaltieri M, Porrini V, Tessari I, Poliani PL, Missale C, Borroni B, Padovani A, Bubacco L, Pizzi M, Spano PF, Bellucci A (2018) Synapsin III is a key component of α-synuclein fibrils in Lewy bodies of PD brains. Brain Pathol 28(6):875–888. https://doi.org/10.1111/bpa.12587

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Atias M, Tevet Y, Sun J, Stavsky A, Tal S, Kahn J, Roy S, Gitler D (2019) Synapsins regulate α-synuclein functions. Proc Natl Acad Sci U S A 166(23):11116–11118. https://doi.org/10.1073/pnas.1903054116

    CAS  Article  Google Scholar 

  130. Cao M, Wu Y, Ashrafi G, McCartney AJ, Wheeler H, Bushong EA, Boassa D, Ellisman MH, Ryan TA, De Camilli P (2017) Parkinson sac domain mutation in synaptojanin 1 impairs clathrin uncoating at synapses and triggers dystrophic changes in dopaminergic axons. Neuron 93(4):882–896. https://doi.org/10.1016/j.neuron.2017.01.019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Bento CF, Ashkenazi A, Jimenez-Sanchez M, Rubinsztein DC (2016) The Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun 7(1):1–16. https://doi.org/10.1038/ncomms11803

    CAS  Article  Google Scholar 

  132. Wang C, Kang X, Zhou L, Chai Z, Wu Q, Huang R, Xu H, Hu M, Sun X, Sun S, Li J, Jiao R, Zuo P, Zheng L, Yue Z, Zhou Z (2018) Synaptotagmin-11 is a critical mediator of Parkin-linked neurotoxicity and Parkinson’s disease-like pathology. Nat Commun 9(1):1–14. https://doi.org/10.1038/s41467-017-02593-y

    CAS  Article  Google Scholar 

  133. Garcia-Reitböck P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, Della Corte L, Spano P, Tofaris GK, Goedert M, Spillantini MG (2010) SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain 133(7):2032–2044. https://doi.org/10.1093/brain/awq132

    Article  PubMed  PubMed Central  Google Scholar 

  134. Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M (2013) Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson’s disease, causes behavioral alterations but not neurodegeneration in mice. Mol Brain 6:35. https://doi.org/10.1186/1756-6606-6-35

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Sala G, Stefanoni G, Arosio A, Riva C, Melchionda L, Saracchi E, Fermi S, Brighina L, Ferrarese C (2014) Reduced expression of the chaperone-mediated autophagy carrier hsc70 protein in lymphomonocytes of patients with Parkinson’s disease. Brain Res 1546:46–52. https://doi.org/10.1016/j.brainres.2013.12.017

    CAS  Article  PubMed  Google Scholar 

  136. Sala G, Marinig D, Arosio A, Ferrarese C (2016) Role of chaperone-mediated autophagy dysfunctions in the pathogenesis of Parkinson’s disease. Front Mol Neurosci 9:157. https://doi.org/10.3389/fnmol.2016.00157

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors sincerely acknowledge Government Shahid Gend Singh College, Charama, for providing facilities to Abhishek Kumar Mishra.

Author information

Authors and Affiliations

Authors

Contributions

AKM contributed to literature search, review design, manuscript preparation, and editing. AD contributed to manuscript preparation and editing.

Corresponding author

Correspondence to Abhishek Kumar Mishra.

Ethics declarations

Conflict of interest

The authors in the manuscript declare that they do not have any conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mishra, A.K., Dixit, A. Dopaminergic Axons: Key Recitalists in Parkinson’s Disease. Neurochem Res 47, 234–248 (2022). https://doi.org/10.1007/s11064-021-03464-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03464-1

Keywords

  • Parkinson's disease
  • Axon degeneration
  • Mitochondrial dynamics
  • Synaptic homeostasis
  • Ca2+