Preferencje help
Widoczny [Schowaj] Abstrakt
Liczba wyników
2019 | 79 | 3 |

Tytuł artykułu

The interplay between parkin and alpha‑synuclein; possible implications for the pathogenesis of Parkinson’s disease

Warianty tytułu

Języki publikacji



Parkin and alpha‑synuclein (α‑syn) are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Oligomerization/ aggregation and excessive secretion of α‑syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of α‑syn. This is in addition to parkin’s role in counteracting the more distant effects of α‑syn on cellular survival by altering proteasomal, autophagic, and calpain‑mediated protein degradation pathways that can reduce α‑syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena – processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of α‑syn by controlling its post‑translational modifications. On the other hand, recent research has shown that α‑syn oligomers affect the expression, post‑translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross‑talk between parkin and α‑syn in PD. The physical and functional interactions between α‑syn and parkin, which have been incompletely characterized to‑date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the therapy of PD.

Słowa kluczowe








Opis fizyczny



  • Department of Cellular Signaling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
  • Department of Regenerative Medicine, Preclinical Research Centre (CePT), Medical University of Warsaw, Warsaw, Poland
  • Department of Cellular Signaling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
  • Department of Cellular Signaling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland


  • Adamczyk A, Czapski GA, Jeśko H, Strosznajder RP (2005a) Non A beta component of Alzheimer’s disease amyloid and amyloid beta peptides evoked poly(ADP‑ribose) polymerase‑dependent release of apoptosis‑inducing factor from rat brain mitochondria. J Physiol Pharmacol 56: 5–13.
  • Adamczyk A, Czapski GA, Kaźmierczak A, Strosznajder JB (2009) Effect of N‑methyl‑D‑aspartate (NMDA) receptor antagonists on alpha‑synuclein‑evoked neuronal nitric oxide synthase activation in the rat brain. Pharmacol Rep 61: 1078–1085.
  • Adamczyk A, Kaźmierczak A (2009) Alpha‑synuclein inhibits poly (ADP‑ribose) polymerase‑1 (PARP‑1) activity via NO‑dependent pathway. Folia Neuropathol 47: 247–251.
  • Adamczyk A, Kaźmierczak A, Czapski GA, Strosznajder JB (2010) Alpha‑synuclein induced cell death in mouse hippocampal (HT22) cells is mediated by nitric oxide‑dependent activation of caspase‑3. FEBS Lett 584: 3504–3508.
  • Adamczyk A, Kaźmierczak A, Strosznajder JB (2006) Alpha‑synuclein and its neurotoxic fragment inhibit dopamine uptake into rat striatal synaptosomes. Relationship to nitric oxide. Neurochem Int 49: 407–412.
  • Adamczyk A, Solecka J, Strosznajder JB (2005b) Expression of alpha‑synuclein in different brain parts of adult and aged rats. J Physiol Pharmacol 56: 29–37.
  • Allen Reish HE, Standaert DG (2015) Role of α‑synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 5: 1–19.
  • Ashrafi G, Schwarz TL (2015) PINK1‑ and PARK2‑mediated local mitophagy in distal neuronal axons. Autophagy 11: 187–189.
  • Beyer K, Ariza A (2013) α‑Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. Mol Neurobiol 47: 509–524.
  • Chakraborty J, Basso V, Ziviani E (2017) Post translational modification of Parkin. Biol Direct 12: 6. Chan NC, Chan DC (2011) Parkin uses the UPS to ship off dysfunctional mitochondria. Autophagy 7: 771–772.
  • Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci 55: 101–14.
  • Chen J, Ren Y, Gui C, Zhao M, Wu X, Mao K, Li W, Zou F (2018) Phosphorylation of Parkin at serine 131 by p38 MAPK promotes mitochondrial dysfunction and neuronal death in mutant A53T α‑synuclein model of Parkinson’s disease. Cell Death Dis 9: 700.
  • Chiba‑Falek O, Kowalak JA, Smulson ME, Nussbaum RL (2005) Regulation of alpha‑synuclein expression by poly (ADP ribose) polymerase‑1 (PARP‑1) binding to the NACP‑Rep1 polymorphic site upstream of the SNCA gene. Am J Hum Genet 76: 478–92.
  • Choubey  V, Safiulina D, Vaarmann A, Cagalinec  M, Wareski P, Kuum  M, Zharkovsky A, Kaasik A (2011) Mutant A53T alpha‑synuclein induces neuronal death by increasing mitochondrial autophagy. J  Biol Chem 286: 10814–10824.
  • Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha‑synuclein‑interacting protein, synphilin‑1: implications for Lewy‑body formation in Parkinson disease. Nat Med 7: 1144–1150.
  • Coppedè F (2012) Genetics and epigenetics of Parkinson’s disease. ScientificWorldJournal 2012: 489830.
  • Costa CA da, Sunyach C, Giaime E, West A, Corti O, Brice A, Safe S, Abou‑Sleiman PM, Wood NW, Takahashi H, Goldberg MS, Shen J, et al. (2009) Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nat Cell Biol 11: 1370–3175.
  • Czapski GA, Gąssowska M, Wilkaniec A, Cieślik M, Adamczyk A (2013) Extracellular alpha‑synuclein induces calpain‑dependent overactivation of cyclin‑dependent kinase 5 in vitro. FEBS Lett 587: 3135–3141.
  • Damiano  M, Gautier CA, Bulteau A‑L, Ferrando‑Miguel R, Gouarne C, Paoli MG, Pruss R, Auchère F, L’Hermitte‑Stead C, Bouillaud F, Brice A, Corti O, Lombès A (2014) Tissue‑ and cell‑specific mitochondrial defect in Parkin‑deficient mice. PLoS One 9: e99898.
  • Danielson SR, Held JM, Schilling B, Oo M, Gibson BW, Andersen JK (2009) Preferentially increased nitration of alpha‑synuclein at tyrosine‑39 in a cellular oxidative model of Parkinson’s disease. Anal Chem 81: 7823–7828.
  • Dawson TM, Dawson VL (2014) Parkin plays a role in sporadic Parkinson’s disease. Neurodegener Dis 13: 69–71. Deas E, Cremades N, Angelova PR, Ludtmann MHR, Yao Z, Chen S, Horrocks  MH, Banushi B, Little D, Devine MJ, Gissen P, Klenerman D, Dobson CM, Wood NW, Gandhi S, Abramov AY (2016) Alpha‑synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid Redox Signal 24: 376–391.
  • Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron‑to‑neuron transmission of alpha‑synuclein. Proc Natl Acad Sci 106: 13010–13015.
  • de Vries RLA, Przedborski S (2013) Mitophagy and Parkinson’s disease: Be eaten to stay healthy. Mol Cell Neurosci 55: 37–43.
  • Duka T, Duka V, Joyce JN, Sidhu A (2009) Alpha‑Synuclein contributes to GSK‑3beta‑catalyzed Tau phosphorylation in Parkinson’s disease models. FASEB J 23: 2820–2830.
  • Duplan E, Sevalle J, Viotti J, Goiran T, Bauer C, Renbaum P, Levy‑Lahad E, Gautier CA, Corti O, Leroudier N, Checler F, Costa CA da (2013) Parkin differently regulates presenilin‑1 and presenilin‑2 functions by direct control of their promoter transcription. J Mol Cell Biol 5: 132–142.
  • Esteves AR, Gozes I, Cardoso SM (2014) The rescue of microtubule‑dependent traffic recovers mitochondrial function in Parkinson’s disease. Biochim Biophys Acta 1842: 7–21.
  • Fallon  L, Bélanger CML, Corera AT, Kontogiannea  M, Regan‑Klapisz E, Moreau F, Voortman J, Haber M, Rouleau G, Thorarinsdottir T, Brice A, van Bergen En Henegouwen PMP, Fon EA (2006) A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K‑Akt signalling. Nat Cell Biol 8: 834–842.
  • Farrer  M, Kachergus J, Forno  L, Lincoln S, Wang D‑S, Hulihan  M, Maraganore  D, Gwinn‑Hardy K, Wszolek Z, Dickson D, Langston JW (2004) Comparison of kindreds with parkinsonism and alpha‑synuclein genomic multiplications. Ann Neurol 55: 174–179.
  • Farrer  M, Wavrant‑De Vrieze F, Crook R, Boles  L, Perez‑Tur J, Hardy J, Johnson WG, Steele J, Maraganore D, Gwinn K, Lynch T (1998) Low frequency of α‑synuclein mutations in familial Parkinson’s disease. Ann Neurol 43: 394–397.
  • Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Paola M Di, Dell’aquila C, Mari M De, Ferranini E, Bonifati V, et al. (2014) Effect of resveratrol on mitochondrial function: implications in parkin‑associated familiar Parkinson’s disease. Biochim Biophys Acta 1842: 902–915.
  • Frank‑Cannon TC, Tran T, Ruhn KA, Martinez TN, Hong J, Marvin  M, Hartley  M, Treviño I, O’Brien DE, Casey B, Goldberg MS, Tansey MG (2008) Parkin deficiency increases vulnerability to inflammation‑related nigral degeneration. J Neurosci 28: 10825–10834.
  • Gąssowska M, Czapski GA, Pająk B, Cieślik M, Lenkiewicz AM, Adamczyk A (2014) Extracellular α‑synuclein leads to microtubule destabilization via GSK‑3β‑dependent Tau phosphorylation in PC12 cells. PLoS One 9: e94259.
  • Gatto EM, Riobó NA, Carreras MC, Cherñavsky A, Rubio A, Satz ML, Poderoso JJ (2000) Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson’s disease. Nitric oxide 4: 534–539.
  • Geisler S, Holmström KM, Treis A, Skujat D, Weber SS, Fiesel FC, Kahle PJ, Springer  W (2010) The PINK1/Parkin‑mediated mitophagy is compromised by PD‑associated mutations. Autophagy 6: 871–878.
  • Geldenhuys WJ, Abdelmagid SM, Gallegos PJ, Safadi FF (2014) Parkinson’s disease biomarker: a patent evaluation of WO2013153386. Expert Opin Ther Pat 24: 947–951.
  • Gentile A, Amadoro G, Corsetti V, Ciotti MT, Serafino A, Calissano P (2008) Spontaneous aggregation and altered intracellular distribution of endogenous alpha‑synuclein during neuronal apoptosis. J Alzheimers Dis 13: 151–160.
  • Giasson BI, Duda JE, Murray I V, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha‑synuclein nitration in synucleinopathy lesions. Science 290: 985–989.
  • Giguère N, Pacelli C, Saumure C, Bourque M‑J, 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: 9580–9593.
  • Goers J, Manning‑Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha‑synuclein and its interaction with histones. Biochemistry. 42: 8465–8471.
  • Gómez‑Santos C, Ferrer I, Santidrián AF, Barrachina M, Gil J, Ambrosio S (2003) Dopamine induces autophagic cell death and alpha‑synuclein increase in human neuroblastoma SH‑SY5Y cells. J  Neurosci Res. 73: 341–350.
  • Grassi D, Howard S, Zhou M, Diaz‑Perez N, Urban NT, Guerrero‑Given D, Kamasawa N, Volpicelli‑Daley LA, LoGrasso P, Lasmézas CI (2018) Identification of a highly neurotoxic α‑synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc Natl Acad Sci 115: E2634–2643.
  • Guo JT, Chen AQ, Kong Q, Zhu H, Ma CM, Qin C (2008) Inhibition of vesicular monoamine transporter‑2 activity in alpha‑synuclein stably transfected SH‑SY5Y cells. Cell Mol Neurobiol 28: 35–47.
  • Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt‑Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, et al. (2000) Caspase‑3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci 97: 2875–2880.
  • Hartmann A, Troadec JD, Hunot S, Kikly K, Faucheux BA, Mouatt‑Prigent A, Ruberg M, Agid Y, Hirsch EC (2001) Caspase‑8 is an effector in apoptotic death of dopaminergic neurons in Parkinson’s disease, but pathway inhibition results in neuronal necrosis. J Neurosci 21: 2247–2255.
  • Hasegawa T, Treis A, Patenge N, Fiesel FC, Springer  W, Kahle PJ (2008) Parkin protects against tyrosinase‑mediated dopamine neurotoxicity by suppressing stress‑activated protein kinase pathways. J Neurochem 105: 1700–1715.
  • Henn IH, Bouman  L, Schlehe JS, Schlierf A, Schramm JE, Wegener E, Nakaso K, Culmsee C, Berninger B, Krappmann D, Tatzelt J, Winklhofer KF (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor‑kappaB signaling. J Neurosci 27: 1868–1878.
  • Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K, Shokat KM (2013) A neo‑substrate that amplifies catalytic activity of parkinson’s‑disease‑related kinase PINK1. Cell 154: 737–747.
  • Hwang CJ, Kim YE, Son DJ, Park MH, Choi D‑Y, Park P‑H, Hellström  M, Han SB, Oh KW, Park EK, Hong JT (2017) Parkin deficiency exacerbate ethanol‑induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function. Redox Biol 11: 456–468.
  • Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891–902.
  • Itier J‑M, Ibanez P, Mena MA, Abbas N, Cohen‑Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, et al. (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12: 2277–2291.
  • Jang A, Lee HJ, Suk JE, Jung JW, Kim KP, Lee SJ (2010) Non‑classical exocytosis of alpha‑synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113: 1263–1274.
  • Jęśko H, Lenkiewicz AM, Adamczyk A (2017) Treatments and compositions targeting α‑synuclein: a  patent review (2010–2016). Expert Opin Ther Pat 27: 427–438.
  • Jiang H, Jiang Q, Liu W, Feng J (2006) Parkin Suppresses the Expression of Monoamine Oxidases. J Biol Chem 281: 8591–8599.
  • Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K, Yan Z, Feng J (2012) Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun 3: 668.
  • Jin H, Kanthasamy A, Ghosh A, Anantharam  V, Kalyanaraman B, Kanthasamy  AG (2014) Mitochondria‑targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta 1842: 1282–1294.
  • Jin SM, Youle RJ (2013) The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin‑mediated mitophagy of polarized mitochondria. Autophagy 9: 1750–1757.
  • Kam TI, Mao X, Park H, Chou SC, Karuppagounder SS, Umanah GE, Yun SP, Brahmachari S, Panicker N, Chen R, Andrabi SA, Qi C, Poirier GG, Pletnikova O, Troncoso JC, Bekris LM, Leverenz JB, Pantelyat A, Ko HS, Rosenthal LS, Dawson TM, Dawson VL (2018) Poly(ADP‑ribose) drives pathologic α‑synuclein neurodegeneration in Parkinson’s disease. Science 362: pii: eaat8407.
  • Kamp F, Exner N, Lutz AK, Wender N, Hegermann J, Brunner B, Nuscher B, Bartels T, Giese A, Beyer K, Eimer S, Winklhofer KF, et al. (2010) Inhibition of mitochondrial fusion by α‑synuclein is rescued by PINK1, Parkin and DJ‑1. EMBO J 29: 3571–3589.
  • Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MMK (2014) Parkin is activated by PINK1‑dependent phosphorylation of ubiquitin at Ser65. Biochem J 460: 127–141.
  • Khan SH, Zhao D, Shah SZA, Hassan MF, Zhu T, Song Z, Zhou X, Yang  L (2017) Parkin overexpression ameliorates PrP106–126‑induced neurotoxicity via enhanced autophagy in N2a cells. Cell Mol Neurobiol 37: 717–728.
  • Khandelwal PJ, Dumanis SB, Feng LR, Maguire‑Zeiss K, Rebeck G, Lashuel HA, Moussa CE (2010) Parkinson‑related parkin reduces α‑Synuclein phosphorylation in a gene transfer model. Mol Neurodegener 5: 47.
  • Kim SJ, Sung JY, Um JW, Hattori N, Mizuno Y, Tanaka K, Paik SR, Kim J, Chung KC (2003) Parkin cleaves intracellular alpha‑synuclein inclusions via the activation of calpain. J Biol Chem 278: 41890–41899.
  • Koch Y, Helferich AM, Steinacker P, Oeckl P, Walther P, Weishaupt JH, Danzer KM, Otto  M (2016) Aggregated α‑Synuclein Increases SOD1 Oligomerization in a Mouse Model of Amyotrophic Lateral Sclerosis. Am J Pathol 186: 2152–2161.
  • Koo HJ, Yang JE, Park JH, Lee D, Paik SR (2013) α‑Synuclein‑mediated defense against oxidative stress via modulation of glutathione peroxidase. Biochim Biophys Acta 1834: 972–976.
  • Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H, Matsumoto T (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15: 883–895.
  • LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11: 1214–1221.
  • Lee Y, Karuppagounder SS, Shin JH, Lee YI, Ko HS, Swing D, Jiang H, Kang SU, Lee BD, Kang HC, Kim D, Tessarollo L, Dawson VL, Dawson TM (2013) Parthanatos mediates AIMP2‑activated age‑dependent dopaminergic neuronal loss. Nat Neurosci 16: 1392–1400.
  • Lee Y, Kang HC, Lee BD, Lee Y‑I, Kim YP, Shin J‑H (2014) Poly (ADP‑ribose) in the pathogenesis of Parkinson’s disease. BMB Rep 47: 424–432.
  • Leong SL, Pham CLL, Galatis D, Fodero‑Tavoletti MT, Perez K, Hill AF, Masters CL, Ali FE, Barnham KJ, Cappai R (2009) Formation of dopamine‑mediated alpha‑synuclein‑soluble oligomers requires methionine oxidation. Free Radic Biol Med 46: 1328–1337.
  • Lewis KA, Su Y, Jou O, Ritchie C, Foong C, Hynan LS, White CL, Thomas PJ, Hatanpaa KJ (2010) Abnormal neurites containing C‑terminally truncated alpha‑synuclein are present in Alzheimer’s disease without conventional Lewy body pathology. Am J Pathol 177: 3037–3050.
  • Li T, Feng Y, Yang R, Wu L, Li R, Huang L, Yang Q, Chen J (2018) Salidroside Promotes the Pathological α‑Synuclein Clearance Through Ubiquitin‑Proteasome System in SH‑SY5Y Cells. Front Pharmacol 9: 377.
  • Li W, Jiang H, Song N, Xie J (2011) Oxidative stress partially contributes to iron‑induced α‑synuclein aggregation in SK‑N‑SH cells. Neurotox Res 19: 435–442.
  • Lim KL, Ng XH, Grace LGY, Yao TP (2012) Mitochondrial dynamics and Parkinson’s disease: focus on parkin. Antioxid Redox Signal 16: 935–949.
  • Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha‑synuclein and the proteasome in alpha‑synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280: 22670–22678.
  • Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, Millan I, Shen A, Saxton W, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B 2012) Parkinson’s disease‑associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet 8: e1002537.
  • Liu X, Hebron  M, Shi  W, Lonskaya I, Moussa CE‑H (2019) Ubiquitin specific protease‑13 independently regulates parkin ubiquitination and alpha‑synuclein clearance in alpha‑synucleinopathies. Hum Mol Genet 28: 548–560.
  • Liu Z, Yu Y, Li X, Ross CA, Smith WW (2011) Curcumin protects against A53T alpha‑synuclein‑induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res 63: 439–444.
  • Lonskaya I, Hebron ML, Algarzae NK, Desforges N, Moussa CE‑H (2013) Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease. Neuroscience 232: 90–105.
  • Machida Y, Chiba T, Takayanagi A, Tanaka Y, Asanuma  M, Ogawa N, Koyama  A, Iwatsubo T, Ito S, Jansen PH, Shimizu N, Tanaka K, et al. (2005) Common anti‑apoptotic roles of parkin and alpha‑synuclein in human dopaminergic cells. Biochem Biophys Res Commun 332: 233–240.
  • Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease α‑synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26: 41–50.
  • Martinez JH, Alaimo A, Gorojod RM, Porte Alcon S, Fuentes F, Coluccio Leskow F, Kotler ML (2018) Drp‑1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH‑SY5Y cells overexpressing alpha‑synuclein. Mol Cell Neurosci. 88: 107–117.
  • McLelland G‑L, Goiran T, Yi W, Dorval G, Chen CX, Lauinger ND, Krahn AI, Valimehr S, Rakovic A, Rouiller I, Durcan TM, Trempe J‑F, et al. (2018) Mfn2 ubiquitination by PINK1/parkin gates the p97‑dependent release of ER from mitochondria to drive mitophagy. Elife 7: pii: e32866.
  • Mogi  M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (2000) Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brain. J Neural Transm 107: 335–341.
  • Mor DE, Tsika E, Mazzulli JR, Gould NS, Kim H, Daniels MJ, Doshi S, Gupta P, Grossman JL, Tan VX, Kalb RG, Caldwell KA, Caldwell GA, Wolfe JH, Ischiropoulos H (2017) Dopamine induces soluble α‑synuclein oligomers and nigrostriatal degeneration. Nat Neurosci 20: 1560–1568.
  • Moszczynska A, Saleh J, Zhang H, Vukusic B, Lee FJS, Liu F (2007) Parkin disrupts the alpha‑synuclein/dopamine transporter interaction: consequences toward dopamine‑induced toxicity. J Mol Neurosci 32: 217–227.
  • Moussa CE‑H (2009) Parkin attenuates wild‑type tau modification in the presence of beta‑amyloid and alpha‑synuclein. J Mol Neurosci 37: 25–36.
  • Norris KL, Hao R, Chen L‑F, Lai C‑H, Kapur  M, Shaughnessy PJ, Chou D, Yan  J, Taylor JP, Engelender S, West AE, Lim K‑L, et al. (2015) Conver gence of Parkin, PINK1, and α‑Synuclein on Stress‑induced Mitochondrial Morphological Remodeling. J Biol Chem 290: 13862–13274.
  • Olzmann JA, Li  L, Chudaev  M  V, Chen J, Perez FA, Palmiter RD, Chin L‑S (2007) Parkin‑mediated K63‑linked polyubiquitination targets misfolded DJ‑1 to aggresomes via binding to HDAC6. J Cell Biol 178: 1025–1038. Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG, Hyman BT, Kazantsev AG (2007) Pharmacological inhibition of PARP‑1 reduces alpha‑synuclein‑ and MPP+‑induced cytotoxicity in Parkinson’s disease in vitro models. Biochem Biophys Res Commun 357: 596–602.
  • Paik SR, Lee D, Cho H‑J, Lee E‑N, Chang C‑S (2003) Oxidized glutathione stimulated the amyloid formation of alpha‑synuclein. FEBS Lett 537: 63–67.
  • Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin‑deficient mice. J Biol Chem 279: 18614–18622.
  • Pankratz N, Kissell DK, Pauciulo MW, Halter CA, Rudolph A, Pfeiffer RF, Marder KS, Foroud T, Nichols WC, Parkinson Study Group‑PROGENI Investigators (2009) Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology 73: 279–286.
  • Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha‑synuclein in the regulation of dopamine biosynthesis. J Neurosci 22: 3090–3099.
  • Ponzini E, De Palma A, Cerboni  L, Natalello A, Rossi R, Moons R, Konijnenberg  A, Narkiewicz J, Legname GA, Sobott F, Mauri P, Santambrogio C, Grandori R (2019) Methionine oxidation in α‑synuclein inhibits its propensity for ordered secondary structure. J Biol Chem., in press pii: jbc.RA118.001907.
  • Ren Y, Jiang H, Yang F, Nakaso K, Feng J (2009) Parkin protects dopaminergic neurons against microtubule‑depolymerizing toxins by attenuating microtubule‑associated protein kinase activation. J Biol Chem 284: 4009–4017.
  • Riobó NA, Schöpfer FJ, Boveris AD, Cadenas E, Poderoso JJ (2002) The reaction of nitric oxide with 6‑hydroxydopamine: implications for Parkinson’s disease. Free Radic Biol Med 32: 115–121.
  • Ryan SD, Dolatabadi N, Chan SF, Zhang X, Akhtar MW, Parker J, Soldner F, Sunico CR, Nagar S, Talantova M, Lee B, Lopez K, et al. (2013) Isogenic human iPSC Parkinson’s model shows nitrosative stress‑induced dysfunction in MEF2‑PGC1α transcription. Cell 155: 1351–1364.
  • Ryan BJ, Hoek S, Fon EA, Wade‑Martins R (2015) Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci 40: 200–210.
  • Sánchez MP, Gonzalo I, Avila J, Yébenes JG De (2002) Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation. J Alzheimers Dis 4: 399–404.
  • Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, Ebadi  M (2002) Deferoxamine attenuates iron‑induced oxidative stress and prevents mitochondrial aggregation and alpha‑synuclein translocation in SK‑N‑SH cells in culture. Dev Neurosci 24: 143–153.
  • Scarffe LA, Stevens DA, Dawson VL, Dawson TM (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci 37: 315–324.
  • Seo J‑H, Rah J‑C, Choi SH, Shin JK, Min K, Kim H‑S, Park CH, Kim S, Kim E‑M, Lee S‑H, Lee S, Suh SW, et al. (2002) Alpha‑synuclein regulates neuronal survival via Bcl‑2 family expression and PI3/Akt kinase pathway. FASEB J 16: 1826–1828.
  • Shaltouki A, Hsieh CH, Kim MJ, Wang X (2018) Alpha‑synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson’s models. Acta Neuropathol. 136: 607–620.
  • Shimura H, Mizuno Y, Hattori N (2012) Parkin and Parkinson Disease. Clin Chem 58: 1260–1261.
  • Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a  new form of alpha‑synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293: 263–269.
  • Shin J‑H, Ko HS, Kang H, Lee Y, Lee Y‑I, Pletinkova O, Troconso JC, Dawson VL, Dawson TM (2011) PARIS (ZNF746) repression of PGC‑1α contributes to neurodegeneration in Parkinson’s disease. Cell 144: 689–702.
  • Silva GM, Finley D, Vogel C (2015) K63 polyubiquitination is a new modulator of the oxidative stress response. Nat Struct Mol Biol 22: 116–123.
  • Singleton A, Gwinn‑Hardy K, Sharabi Y, Li ST, Holmes C, Dendi R, Hardy J, Singleton A, Crawley A, Goldstein DS (2004) Association between cardiac denervation and parkinsonism caused by alpha‑synuclein gene triplication. Brain 127: 768–772.
  • Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B (2003) Aggregated and monomeric alpha‑synuclein bind to the S6’ proteasomal protein and inhibit proteasomal function. J  Biol Chem 278: 11753–11759.
  • Su X, Maguire‑Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29: 1690–1701.
  • Taguchi K, Watanabe Y, Tsujimura A, Tanaka M (2016) Brain region‑dependent differential expression of alpha‑synuclein. J  Comp Neurol. 524: 1236–1258.
  • Turnbull S, Tabner BJ, El‑Agnaf OM, Moore S, Davies Y, Allsop D (2001) alpha‑Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med 30: 1163–1170.
  • Uversky VN, Yamin G, Munishkina LA, Karymov MA, Millett IS, Doniach S, Lyubchenko YL, Fink AL (2005) Effects of nitration on the structure and aggregation of α‑synuclein. Mol Brain Res 134: 84–102.
  • Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee Y Il, Dawson VL, Dawson TM, Sen N, Snyder SH (2013) Sulfhydration mediates neuroprotective actions of parkin. Nat Commun 4: 1626.
  • Venderova K, Park DS (2012) Programmed Cell Death in Parkinson’s Disease. Cold Spring Harb Perspect Med 2: a009365.
  • Vercammen L, Perren A Van der, Vaudano E, Gijsbers R, Debyser Z, Haute C Van den, Baekelandt V (2006) Parkin Protects against Neurotoxicity in the 6‑Hydroxydopamine Rat Model for Parkinson’s Disease. Mol Ther 14: 716–723.
  • Vries RLA de, Przedborski S (2013) Mitophagy and Parkinson’s disease: be eaten to stay healthy. Mol Cell Neurosci 55: 37–43.
  • Wang C, Ko HS, Thomas B, Tsang F, Chew KCM, Tay S‑P, Ho MWL, Lim T‑M, Soong T‑W, Pletnikova O, Troncoso J, Dawson VL, et al. (2005) Stress‑induced alterations in parkin solubility promote parkin aggregation and compromise parkin’s protective function. Hum Mol Genet 14: 3885–3897.
  • Wilkaniec A, Lenkiewicz AM, Czapski GA, Jęśko HM, Hilgier  W, Brodzik R, Gąssowska‑Dobrowolska M, Culmsee C, Adamczyk A (2019) Extracellular Alpha‑Synuclein Oligomers Induce Parkin S‑Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology. Mol Neurobiol 56: 125–140.
  • Winslow AR, Rubinsztein DC (2011) The Parkinson disease protein α‑synuclein inhibits autophagy. Autophagy 7: 429–431.
  • Wong YC, Krainc D (2017) α‑synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23: 1–13.
  • Xie W, Chung KKK (2012) Alpha‑synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson’s disease. J Neurochem 122: 404–414.
  • Xu B, Wang F, Wu S‑W, Deng Y, Liu W, Feng S, Yang T‑Y, Xu Z‑F (2014) α‑Synuclein is involved in manganese‑induced ER stress via PERK signal pathway in organotypic brain slice cultures. Mol Neurobiol 49: 399–412.
  • Yamin G, Uversky VN, Fink AL (2003) Nitration inhibits fibrillation of human alpha‑synuclein in vitro by formation of soluble oligomers. FEBS Lett 542: 147–152.
  • Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron‑selective neurotoxicity induced by Pael‑R in Drosophila. Neuron 37: 911–924.
  • Yu Z, Xu X, Xiang Z, Zhou J, Zhang Z, Hu C, He C (2010) Nitrated alpha‑synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats. PLoS One 5: e9956.
  • Yuan Y, Jin J, Yang B, Zhang  W, Hu J, Zhang Y, Chen NH (2008) Overexpressed alpha‑synuclein regulated the nuclear factor‑kappaB signal pathway. Cell Mol Neurobiol 28: 21–33.
  • Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang‑James Y, Kim PD, Hauser MA, Grunblatt E, Moran LB, et al. (2010) PGC‑1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease. Sci Transl Med 2: 52ra73. Zheng X, Hunter T (2013) Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism. Cell Res 23: 886–897.
  • Zhu X, Ma X, Tu Y, Huang M, Liu H, Wang F, Gong J, Wang J, Li X, Chen Q, Shen H, Zhu S, et al., (2017) Parkin regulates translesion DNA synthesis in response to UV radiation. Oncotarget 8: 36423–36437.
  • Zhu Y, Duan C, Lü L, Gao H, Zhao C, Yu S, Uéda K, Chan P, Yang H (2011) α‑Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. Int J Biochem Cell Biol 43: 732–741.

Typ dokumentu



Identyfikator YADDA

JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.