Current treatments for Parkinson's disease fail to modify disease progression, and the underlying pathogenic mechanisms remain elusive. The identification of specific targets responsible for disease will aid in the development of relevant model systems and the discovery of neuroprotective and neurorestorative therapies. Two promising protein candidates, α-synuclein and LRRK2, offer unique insight into the molecular basis of disease and the potential to intervene in pathogenesis. Although multiple lines of evidence support α-synuclein and LRRK2 as robust targets for therapy, the connection between protein function and neurodegeneration is unclear. Technology capable of mitigating α-synuclein and LRRK2 disease-associated function will ultimately be required before the true value of these proteins as therapeutic targets can be discerned. Antioxid. Redox Signal. 11, 2167–2187.
Get full access to this article
View all access options for this article.
References
1.
The Parkinson Study Group PRECEPT Investigators. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology, 69:1480–1490. 2007.
2.
NINDS NET-PD Investigators. A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. Clin Neuropharmacol, 31:141–150. 2008.
AhlskogJE. Beating a dead horse: dopamine and Parkinson disease. Neurology, 69:1701–1711. 2007.
5.
AhnBH, RhimH, KimSY, SungYM, LeeMY, ChoiJY, WolozinB, ChangJS, LeeYH, KwonTK, ChungKC, YoonSH, HahnSJ, KimMS, JoYH, MinDS. alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells. J Biol Chem, 277:12334–12342. 2002.
6.
AlbaniD, PeverelliE, RamettaR, BatelliS, VeschiniL, NegroA, ForloniG. Protective effect of TAT-delivered alpha-synuclein: relevance of the C-terminal domain and involvement of HSP70. FASEB J, 18:1713–1715. 2004.
7.
AndersonJP, WalkerDE, GoldsteinJM, de LaatR, BanducciK, CaccavelloRJ, BarbourR, HuangJ, KlingK, LeeM, DiepL, KeimPS, ShenX, ChatawayT, SchlossmacherMG, SeubertP, SchenkD, SinhaS, GaiWP, ChilcoteTJ. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem, 281:29739–29752. 2006.
8.
AuluckPK, ChanHY, TrojanowskiJQ, LeeVM, BoniniNM. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science, 295:865–868. 2002.
9.
BabaM, NakajoS, TuPH, TomitaT, NakayaK, LeeVM, TrojanowskiJQ, IwatsuboT. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol, 152:879–884. 1998.
10.
BielerS, SotoC. Beta-sheet breakers for Alzheimer's disease therapy. Curr Drug Targets, 5:553–558. 2004.
11.
BiskupS, MooreDJ, CelsiF, HigashiS, WestAB, AndrabiSA, KurkinenK, YuSW, SavittJM, WaldvogelHJ, FaullRL, EmsonPC, TorpR, OttersenOP, DawsonTM, DawsonVL. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol, 60:557–569. 2006.
12.
BiskupS, MooreDJ, ReaA, Lorenz-DeperieuxB, CoombesCE, DawsonVL, DawsonTM, WestAB. Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci, 8:102. 2007.
13.
BiskupS, MuellerJC, SharmaM, LichtnerP, ZimprichA, BergD, WullnerU, IlligT, MeitingerT, GasserT. Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Ann Neurol, 58:905–908. 2005.
14.
BonifatiV, RizzuP, van BarenMJ, SchaapO, BreedveldGJ, KriegerE, DekkerMC, SquitieriF, IbanezP, JoosseM, van DongenJW, VanacoreN, van SwietenJC, BriceA, MecoG, van DuijnCM, OostraBA, HeutinkP. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 299:256–259. 2003.
15.
BorghiR, MarcheseR, NegroA, MarinelliL, ForloniG, ZaccheoD, AbbruzzeseG, TabatonM. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci Lett, 287:65–67. 2000.
16.
BosgraafL, Van HaastertPJ. Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta, 1643:5–10. 2003.
17.
BraakH, GhebremedhinE, RubU, BratzkeH, Del TrediciK. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res, 318:121–134. 2004.
18.
BrownDR. Interactions between metals and alpha-synuclein: function or artefact?FEBS J, 274:3766–3774. 2007.
19.
BussellRJr, EliezerD. A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J Mol Biol, 329:763–778. 2003.
20.
ChanCS, GuzmanJN, IlijicE, MercerJN, RickC, TkatchT, MeredithGE, SurmeierDJ. “Rejuvenation” protects neurons in mouse models of Parkinson's disease. Nature, 447:1081–1086. 2007.
21.
ChandraS, FornaiF, KwonHB, YazdaniU, AtasoyD, LiuX, HammerRE, BattagliaG, GermanDC, CastilloPE, SudhofTC. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A, 101:14966–14971. 2004.
22.
ChenH, O'ReillyEJ, SchwarzschildMA, AscherioA. Peripheral inflammatory biomarkers and risk of Parkinson's disease. Am J Epidemiol, 167:90–95. 2008.
23.
ChenK, HuangJ, GongW, ZhangL, YuP, WangJM. CD40/CD40L dyad in the inflammatory and immune responses in the central nervous system. Cell Mol Immunol, 3:163–169. 2006.
24.
ChenL, FeanyMB. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci, 8:657–663. 2005.
25.
Chiba-FalekO, NussbaumRL. Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet, 10:3101–3109. 2001.
26.
Chiba-FalekO, TouchmanJW, NussbaumRL. Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. Hum Genet, 113:426–431. 2003.
27.
ChoiWS, KruseSE, PalmiterRD, XiaZ. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. Proc Natl Acad Sci U S A, 105:15136–15141. 2008.
28.
ClaytonDF, GeorgeJM. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci, 21:249–254. 1998.
29.
CloughRL, StefanisL. A novel pathway for transcriptional regulation of alpha-synuclein. FASEB J, 21:596–607. 2007.
30.
CohlbergJA, LiJ, UverskyVN, FinkAL. Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from alpha-synuclein in vitro. Biochemistry, 41:1502–1511. 2002.
31.
ColeNB, MurphyDD, GriderT, RueterS, BrasaemleD, NussbaumRL. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. J Biol Chem, 277:6344–6352. 2002.
32.
ConwayKA, RochetJC, BieganskiRM, LansburyPTJr.Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science, 294:1346–1349. 2001.
CrowtherRA, JakesR, SpillantiniMG, GoedertM. Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett, 436:309–312. 1998.
35.
CuervoAM, StefanisL, FredenburgR, LansburyPT, SulzerD. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science, 305:1292–1295. 2004.
36.
DauerW, KholodilovN, VilaM, TrillatAC, GoodchildR, LarsenKE, StaalR, TieuK, SchmitzY, YuanCA, RochaM, Jackson-LewisV, HerschS, SulzerD, PrzedborskiS, BurkeR, HenR. Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A, 99:14524–14529. 2002.
37.
DavidsonWS, JonasA, ClaytonDF, GeorgeJM. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem, 273:9443–9449. 1998.
38.
DedmonMM, ChristodoulouJ, WilsonMR, DobsonCM. Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem, 280:14733–14740. 2005.
39.
DengH, DodsonMW, HuangH, GuoM. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A, 105:14503–14508. 2008.
40.
DevKK, HofeleK, BarbieriS, BuchmanVL, van der PuttenH. Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology, 45:14–44. 2003.
41.
DexterDT, JennerP, SchapiraAH, MarsdenCD. Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia: the Royal Kings and Queens Parkinson's Disease Research Group. Ann Neurol, 32(suppl):S94–S100. 1992.
42.
DexterDT, WellsFR, LeesAJ, AgidF, AgidY, JennerP, MarsdenCD. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J Neurochem, 52:1830–1836. 1989.
DicksonDW, FujishiroH, DelleDonneA, MenkeJ, AhmedZ, KlosKJ, JosephsKA, FrigerioR, BurnettM, ParisiJE, AhlskogJE. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol, 115:437–444. 2008.
45.
DriverJA, KurthT, BuringJE, GazianoJM, LogroscinoG. Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study. Neurology, 70:1423–1430. 2008.
46.
DrobyshevaD, AmeelK, WelchB, EllisonE, ChaichanaK, HoangB, SharmaS, NeckameyerW, SrinakevitchI, MurphyKJ, SchmidA. An optimized method for histological detection of dopaminergic neurons in Drosophila melanogaster. J Histochem Cytochem, 56:1049–1063. 2008.
47.
DudaJE, GiassonBI, ChenQ, GurTL, HurtigHI, SternMB, GollompSM, IschiropoulosH, LeeVM, TrojanowskiJQ. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol, 157:1439–1445. 2000.
48.
El-AgnafOM, JakesR, CurranMD, WallaceA. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease. FEBS Lett, 440:67–70. 1998.
49.
EljaschewitschE, WittingA, MawrinC, LeeT, SchmidtPM, WolfS, HoertnaglH, RaineCS, Schneider-StockR, NitschR, UllrichO. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron, 49:67–79. 2006.
50.
EmadiS, BarkhordarianH, WangMS, SchulzP, SierksMR. Isolation of a human single chain antibody fragment against oligomeric alpha-synuclein that inhibits aggregation and prevents alpha-synuclein-induced toxicity. J Mol Biol, 368:1132–1144. 2007.
51.
EngelenderS. Ubiquitination of alpha-synuclein and autophagy in Parkinson's disease. Autophagy, 4:372–374. 2008.
52.
EtminanM, GillSS, SamiiA. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson's disease: a meta-analysis. Lancet Neurol, 4:362–365. 2005.
53.
FarissMW, ZhangJG. Vitamin E therapy in Parkinson's disease. Toxicology, 189:129–146. 2003.
54.
FarrerM, MaraganoreDM, LockhartP, SingletonA, LesnickTG, de AndradeM, WestA, de SilvaR, HardyJ, HernandezD. alpha-Synuclein gene haplotypes are associated with Parkinson's disease. Hum Mol Genet, 10:1847–1851. 2001.
55.
FeanyMB. Studying human neurodegenerative diseases in flies and worms. J Neuropathol Exp Neurol, 59:847–856. 2000.
56.
FeanyMB, BenderWW. A Drosophila model of Parkinson's disease. Nature, 404:394–398. 2000.
57.
FlowerTR, ChesnokovaLS, FroelichCA, DixonC, WittSN. Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J Mol Biol, 351:1081–1100. 2005.
58.
FortinDL, TroyerMD, NakamuraK, KuboS, AnthonyMD, EdwardsRH. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci, 24:6715–6723. 2004.
59.
FountaineTM, Wade-MartinsR. RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res, 85:351–363. 2007.
60.
FujiwaraH, HasegawaM, DohmaeN, KawashimaA, MasliahE, GoldbergMS, ShenJ, TakioK, IwatsuboT. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol, 4:160–164. 2002.
61.
FunayamaM, HasegawaK, KowaH, SaitoM, TsujiS, ObataF. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol, 51:296–301. 2002.
62.
GalpernWR, CudkowiczME. Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion, 7(suppl):S146–S153. 2007.
GarberK. The second wave in kinase cancer drugs. Nat Biotechnol, 24:127–130. 2006.
65.
GeorgeJM, JinH, WoodsWS, ClaytonDF. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron, 15:361–372. 1995.
66.
GiassonBI, DudaJE, MurrayIV, ChenQ, SouzaJM, HurtigHI, IschiropoulosH, TrojanowskiJQ, LeeVM. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science, 290:985–989. 2000.
67.
GiassonBI, DudaJE, QuinnSM, ZhangB, TrojanowskiJQ, LeeVM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron, 34:521–533. 2002.
68.
GiassonBI, MurrayIV, TrojanowskiJQ, LeeVM. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem, 276:2380–2386. 2001.
69.
GilksWP, Abou-SleimanPM, GandhiS, JainS, SingletonA, LeesAJ, ShawK, BhatiaKP, BonifatiV, QuinnNP, LynchJ, HealyDG, HoltonJL, ReveszT, WoodNW. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet, 365:415–416. 2005.
GloecknerCJ, KinklN, SchumacherA, BraunRJ, O'NeillE, MeitingerT, KolchW, ProkischH, UeffingM. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet, 15:223–232. 2006.
72.
GoedertM. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci, 2:492–501. 2001.
73.
GoersJ, Manning-BogAB, McCormackAL, MillettIS, DoniachS, Di MonteDA, UverskyVN, FinkAL. Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry, 42:8465–8471. 2003.
74.
GoersJ, UverskyVN, FinkAL. Polycation-induced oligomerization and accelerated fibrillation of human alpha-synuclein in vitro. Protein Sci, 12:702–707. 2003.
75.
GorellJM, JohnsonCC, RybickiBA, PetersonEL, RichardsonRJ. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology, 50:1346–1350. 1998.
76.
GreggioE, JainS, KingsburyA, BandopadhyayR, LewisP, KaganovichA, van der BrugMP, BeilinaA, BlackintonJ, ThomasKJ, AhmadR, MillerDW, KesavapanyS, SingletonA, LeesA, HarveyRJ, HarveyK, CooksonMR. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis, 23:329–341. 2006.
77.
GreggioE, LewisPA, van der BrugMP, AhmadR, KaganovichA, DingJ, BeilinaA, BakerAK, CooksonMR. Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. J Neurochem, 102:93–102. 2007.
78.
GreggioE, ZambranoI, KaganovichA, BeilinaA, TaymansJM, DanielsV, LewisP, JainS, DingJ, SyedA, ThomasKJ, BaekelandtV, CooksonMR. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem, 283:16906–16914. 2008.
79.
GuoL, GandhiPN, WangW, PetersenRB, Wilson-DelfosseAL, ChenSG. The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res, 313:3658–3670. 2007.
80.
HamamichiS, RivasRN, KnightAL, CaoS, CaldwellKA, CaldwellGA. Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc Natl Acad Sci U S A, 105:728–733. 2008.
81.
HanBS, IacovittiL, KatanoT, HattoriN, SeolW, KimKS. Expression of the LRRK2 gene in the midbrain dopaminergic neurons of the substantia nigra. Neurosci Lett, 442:190–194. 2008.
82.
HanH, WeinrebPH, LansburyPTJr.The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease?Chem Biol, 2:163–169. 1995.
83.
HarleyA, CooperJM, SchapiraAH. Iron induced oxidative stress and mitochondrial dysfunction: relevance to Parkinson's disease. Brain Res, 627:349–353. 1993.
84.
HashimotoM, HsuLJ, XiaY, TakedaA, SiskA, SundsmoM, MasliahE. Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport, 10:717–721. 1999.
85.
HashimotoM, RockensteinE, ManteM, CrewsL, Bar-OnP, GageFH, MarrR, MasliahE. An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model. Gene Ther, 11:1713–1723. 2004.
86.
HelyMA, MorrisJG, ReidWG, TrafficanteR. Sydney multicenter study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord, 20:190–199. 2005.
87.
HigashiS, BiskupS, WestAB, TrinkausD, DawsonVL, FaullRL, WaldvogelHJ, AraiH, DawsonTM, MooreDJ, EmsonPC. Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Res, 1155:208–219. 2007.
88.
HirohataM, OnoK, MorinagaA, YamadaM. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology, 54:620–627. 2008.
89.
HokensonMJ, UverskyVN, GoersJ, YaminG, MunishkinaLA, FinkAL. Role of individual methionines in the fibrillation of methionine-oxidized alpha-synuclein. Biochemistry, 43:4621–4633. 2004.
90.
HorstinkMW, van EngelenBG. The effect of coenzyme Q10 therapy in Parkinson disease could be symptomatic. Arch Neurol, 60:1170–1172. 2003author reply 1172–1173.
91.
HulihanMM, Ishihara-PaulL, KachergusJ, WarrenL, AmouriR, ElangoR, PrinjhaRK, UpmanyuR, KefiM, ZouariM, SassiSB, YahmedSB, El Euch-FayecheG, MatthewsPM, MiddletonLT, GibsonRA, HentatiF, FarrerMJ. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol, 7:591–594. 2008.
92.
HunotS, HirschEC. Neuroinflammatory processes in Parkinson's disease. Ann Neurol, 53,suppl 3:S49–S58. 2003discussion S58–S60.
ImaiY, GehrkeS, WangHQ, TakahashiR, HasegawaK, OotaE, LuB. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J, 27:2432–2443. 2008.
95.
ItoG, OkaiT, FujinoG, TakedaK, IchijoH, KatadaT, IwatsuboT. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry, 46:1380–1388. 2007.
96.
IwaiA, MasliahE, YoshimotoM, GeN, FlanaganL, de SilvaHA, KittelA, SaitohT. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron, 14:467–475. 1995.
97.
IwataA, MaruyamaM, KanazawaI, NukinaN. alpha-Synuclein affects the MAPK pathway and accelerates cell death. J Biol Chem, 276:45320–45329. 2001.
98.
IwataA, MiuraS, KanazawaI, SawadaM, NukinaN. alpha-Synuclein forms a complex with transcription factor Elk-1. J Neurochem, 77:239–252. 2001.
99.
JaleelM, NicholsRJ, DeakM, CampbellDG, GillardonF, KnebelA, AlessiDR. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J, 405:307–317. 2007.
100.
JankovicJ. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry, 79:368–376. 2008.
101.
JellingerKA. A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta, 2008Aug 5 [Epub ahead of print].
102.
JencoJM, RawlingsonA, DanielsB, MorrisAJ. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. Biochemistry, 37:4901–4909. 1998.
103.
JensenPH, HojrupP, HagerH, NielsenMS, JacobsenL, OlesenOF, GliemannJ, JakesR. Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC. Biochem J, 323:539–546. 1997.
104.
JensenPH, NielsenMS, JakesR, DottiCG, GoedertM. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. J Biol Chem, 273:26292–26294. 1998.
105.
JoE, McLaurinJ, YipCM, St George-HyslopP, FraserPE. alpha-Synuclein membrane interactions and lipid specificity. J Biol Chem, 275:34328–34334. 2000.
106.
JohnsonWG, HodgeSE, DuvoisinR. Twin studies and the genetics of Parkinson's disease: a reappraisal. Mov Disord, 5:187–194. 1990.
107.
JunnE, RonchettiRD, QuezadoMM, KimSY, MouradianMM. Tissue transglutaminase-induced aggregation of alpha-synuclein: implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A, 100:2047–2052. 2003.
108.
KahlePJ, NeumannM, OzmenL, HaassC. Physiology and pathophysiology of alpha-synuclein: cell culture and transgenic animal models based on a Parkinson's disease-associated protein. Ann N Y Acad Sci, 920:33–41. 2000.
109.
KalkondeYV, MorganWW, SigalaJ, MaffiSK, CondelloC, KuzielW, AhujaSS, AhujaSK. Chemokines in the MPTP model of Parkinson's disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Brain Res, 1128:1–11. 2007.
110.
KandaS, BishopJF, EglitisMA, YangY, MouradianMM. Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience, 97:279–284. 2000.
111.
KimTD, PaikSR, YangCH. Structural and functional implications of C-terminal regions of alpha-synuclein. Biochemistry, 41:13782–13790. 2002.
112.
KimYS, ChoiDH, BlockML, LorenzlS, YangL, KimYJ, SugamaS, ChoBP, HwangO, BrowneSE, KimSY, HongJS, BealMF, JohTH. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J, 21:179–187. 2007.
113.
KimYS, LaurineE, WoodsW, LeeSJ. A novel mechanism of interaction between alpha-synuclein and biological membranes. J Mol Biol, 360:386–397. 2006.
114.
KirikD, RosenbladC, BurgerC, LundbergC, JohansenTE, MuzyczkaN, MandelRJ, BjorklundA. Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci, 22:2780–2791. 2002.
115.
KitadaT, AsakawaS, HattoriN, MatsumineH, YamamuraY, MinoshimaS, YokochiM, MizunoY, ShimizuN. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392:605–608. 1998.
116.
KlegerisA, GiassonBI, ZhangH, MaguireJ, PelechS, McGeerPL. Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB J, 20:2000–2008. 2006.
117.
KlegerisA, McGeerEG, McGeerPL. Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol, 20:351–357. 2007.
118.
KlegerisA, PelechS, GiassonBI, MaguireJ, ZhangH, McGeerEG, McGeerPL. Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging, 29:739–752. 2008.
119.
KleinRL, KingMA, HambyME, MeyerEM. Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther, 13:605–612. 2002.
120.
KorrD, ToschiL, DonnerP, PohlenzHD, KreftB, WeissB. LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. Cell Signal, 18:910–920. 2006.
121.
KrugerR, KuhnW, MullerT, WoitallaD, GraeberM, KoselS, PrzuntekH, EpplenJT, ScholsL, RiessO. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet, 18:106–108. 1998.
122.
KuhnM, HaebigK, BoninM, NinkinaN, BuchmanVL, PothsS, RiessO. Whole genome expression analyses of single- and double-knock-out mice implicate partially overlapping functions of alpha- and gamma-synuclein. Neurogenetics, 8:71–81. 2007.
123.
KuwaharaT, KoyamaA, KoyamaS, YoshinaS, RenCH, KatoT, MitaniS, IwatsuboT. A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in {alpha}-synuclein transgenic C. elegans. Hum Mol Genet, 17:2997–3009. 2008.
124.
LangstonJW. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol, 59:591–596. 2006.
125.
LangstonJW, FornoLS, TetrudJ, ReevesAG, KaplanJA, KarlukD. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol, 46:598–605. 1999.
126.
LeeJT, WheelerTC, LiL, ChinLS. Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet, 17:906–917. 2008.
127.
LeeM, HyunD, HalliwellB, JennerP. Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. J Neurochem, 76:998–1009. 2001.
128.
LeeMK, StirlingW, XuY, XuX, QuiD, MandirAS, DawsonTM, CopelandNG, JenkinsNA, PriceDL. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53: T thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A, 99:8968–8973. 2002.
129.
LeeSB, KimW, LeeS, ChungJ. Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun, 358:534–539. 2007.
130.
LesageS, DurrA, TazirM, LohmannE, LeuteneggerAL, JaninS, PollakP, BriceA. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med, 354:422–423. 2006.
131.
LewisPA, GreggioE, BeilinaA, JainS, BakerA, CooksonMR. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun, 357:668–671. 2007.
LiJY, Henning JensenP, DahlstromA. Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience, 113:463–478. 2002.
134.
LiX, TanYC, PouloseS, OlanowCW, HuangXY, YueZ. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem, 103:238–247. 2007.
135.
LianiE, EyalA, AvrahamE, ShemerR, SzargelR, BergD, BornemannA, RiessO, RossCA, RottR, EngelenderS. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc Natl Acad Sci U S A, 101:5500–5505. 2004.
136.
LimousinP, Martinez-TorresI. Deep brain stimulation for Parkinson's disease. Neurotherapeutics, 5:309–319. 2008.
137.
LiuDM, JinL, WangH, ZhaoHY, ZhaoCL, YangH. RNA interference mediated silencing of alpha-synuclein in MN9D cells and its effects on cell viability. Neurosci Bull, 24:96–104. 2008.
LiuZ, WangX, YuY, LiX, WangT, JiangH, RenQ, JiaoY, SawaA, MoranT, RossCA, MontellC, SmithWW. A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A, 105:2693–2698. 2008.
140.
Lo BiancoC, DeglonN, PralongW, AebischerP. Lentiviral nigral delivery of GDNF does not prevent neurodegeneration in a genetic rat model of Parkinson's disease. Neurobiol Dis, 17:283–289. 2004.
141.
Lo BiancoC, RidetJL, SchneiderBL, DeglonN, AebischerP. alpha-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc Natl Acad Sci U S A, 99:10813–10818. 2002.
142.
Lo BiancoC, SchneiderBL, BauerM, SajadiA, BriceA, IwatsuboT, AebischerP. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A, 101:17510–17515. 2004.
143.
LuX, BingG, HaggT. Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience, 97:285–291. 2000.
144.
LuckingCB, BriceA. Alpha-synuclein and Parkinson's disease. Cell Mol Life Sci, 57:1894–1908. 2000.
145.
MacLeodD, DowmanJ, HammondR, LeeteT, InoueK, AbeliovichA. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron, 52:587–593. 2006.
146.
MandalPK, PettegrewJW, MasliahE, HamiltonRL, MandalR. Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochem Res, 31:1153–1162. 2006.
147.
Manning-BogAB, McCormackAL, PurisaiMG, BolinLM, Di MonteDA. Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci, 23:3095–3099. 2003.
MariesE, DassB, CollierTJ, KordowerJH, Steece-CollierK. The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci, 4:727–738. 2003.
150.
MarinI. Ancient origin of the Parkinson disease gene LRRK2. J Mol Evol, 67:41–50. 2008.
151.
MasliahE, RockensteinE, AdameA, AlfordM, CrewsL, HashimotoM, SeubertP, LeeM, GoldsteinJ, ChilcoteT, GamesD, SchenkD. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron, 46:857–868. 2005.
152.
MasliahE, RockensteinE, VeinbergsI, MalloryM, HashimotoM, TakedaA, SagaraY, SiskA, MuckeL. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science, 287:1265–1269. 2000.
153.
MataIF, WedemeyerWJ, FarrerMJ, TaylorJP, GalloKA. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci, 29:286–293. 2006.
154.
MatsuokaY, VilaM, LincolnS, McCormackA, PiccianoM, LaFrancoisJ, YuX, DicksonD, LangstonWJ, McGowanE, FarrerM, HardyJ, DuffK, PrzedborskiS, Di MonteDA. Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis, 8:535–539. 2001.
155.
McCoyMK, MartinezTN, RuhnKA, SzymkowskiDE, SmithCG, BottermanBR, TanseyKE, TanseyMG. Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J Neurosci, 26:9365–9375. 2006.
156.
McGeerPL, ItagakiS, BoyesBE, McGeerEG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology, 38:1285–1291. 1988.
157.
McGeerPL, SchwabC, ParentA, DoudetD. Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol, 54:599–604. 2003.
158.
McLeanPJ, KawamataH, HymanBT. Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience, 104:901–912. 2001.
159.
McLeanPJ, KawamataH, RibichS, HymanBT. Membrane association and protein conformation of alpha-synuclein in intact neurons: effect of Parkinson's disease-linked mutations. J Biol Chem, 275:8812–8816. 2000.
160.
McLeanPJ, KawamataH, ShariffS, HewettJ, SharmaN, UedaK, BreakefieldXO, HymanBT. TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem, 83:846–854. 2002.
161.
MelamedE, ZivI, DjaldettiR. Management of motor complications in advanced Parkinson's disease. Mov Disord, 22,suppl 17:S379–S384. 2007.
162.
MelroseH, LincolnS, TyndallG, DicksonD, FarrerM. Anatomical localization of leucine-rich repeat kinase 2 in mouse brain. Neuroscience, 139:791–794. 2006.
163.
MillerRM, KiserGL, Kaysser-KranichT, CasaceliC, CollaE, LeeMK, PalaniappanC, FederoffHJ. Wild-type and mutant alpha-synuclein induce a multi-component gene expression profile consistent with shared pathophysiology in different transgenic mouse models of PD. Exp Neurol, 204:421–432. 2007.
164.
MizunoT, KunoR, NittaA, NabeshimaT, ZhangG, KawanokuchiJ, WangJ, JinS, TakeuchiH, SuzumuraA. Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes. Brain Res, 1066:78–85. 2005.
165.
MonahanAJ, WarrenM, CarveyPM. Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis. Cell Transplant, 17:363–372. 2008.
166.
MuellerJC, FuchsJ, HoferA, ZimprichA, LichtnerP, IlligT, BergD, WullnerU, MeitingerT, GasserT. Multiple regions of alpha-synuclein are associated with Parkinson's disease. Ann Neurol, 57:535–541. 2005.
167.
Mukaetova-LadinskaEB, MilneJ, AndrasA, Abdel-AllZ, CerejeiraJ, GreallyE, RobsonJ, JarosE, PerryR, McKeithIG, BrayneC, XuerebJ, CleghornA, DohertyJ, McIntoshG, MiltonI. Alpha- and gamma-synuclein proteins are present in cerebrospinal fluid and are increased in aged subjects with neurodegenerative and vascular changes. Dement Geriatr Cogn Disord, 26:32–42. 2008.
168.
MullerG. Medicinal chemistry of target family-directed masterkeys. Drug Discov Today, 8:681–691. 2003.
169.
MunishkinaLA, HenriquesJ, UverskyVN, FinkAL. Role of protein-water interactions and electrostatics in alpha-synuclein fibril formation. Biochemistry, 43:3289–3300. 2004.
170.
MurrayIV, GiassonBI, QuinnSM, KoppakaV, AxelsenPH, IschiropoulosH, TrojanowskiJQ, LeeVM. Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry, 42:8530–8540. 2003.
NicholsWC, PankratzN, HernandezD, Paisan-RuizC, JainS, HalterCA, MichaelsVE, ReedT, RudolphA, ShultsCW, SingletonA, ForoudT. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet, 365:410–412. 2005.
173.
OkunoT, NakatsujiY, KumanogohA, MoriyaM, IchinoseH, SumiH, FujimuraH, KikutaniH, SakodaS. Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD 40: relevance to Parkinson's disease. J Neurosci Res, 81:874–882. 2005.
174.
OnoK, HirohataM, YamadaM. Anti-fibrillogenic and fibril-destabilizing activities of anti-Parkinsonian agents for alpha-synuclein fibrils in vitro. J Neurosci Res, 85:1547–1557. 2007.
175.
Ostrerova-GoltsN, PetrucelliL, HardyJ, LeeJM, FarerM, WolozinB. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci, 20:6048–6054. 2000.
176.
OstrerovaN, PetrucelliL, FarrerM, MehtaN, ChoiP, HardyJ, WolozinB. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci, 19:5782–5791. 1999.
OuteiroTF, PutchaP, TetzlaffJE, SpoelgenR, KokerM, CarvalhoF, HymanBT, McLeanPJ. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS ONE, 3:e1867. 2008.
179.
OzeliusLJ, SenthilG, Saunders-PullmanR, OhmannE, DeligtischA, TagliatiM, HuntAL, KleinC, HenickB, HailpernSM, LiptonRB, Soto-ValenciaJ, RischN, BressmanSB. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med, 354:424–425. 2006.
180.
PaikSR, ShinHJ, LeeJH. Metal-catalyzed oxidation of alpha-synuclein in the presence of copper(II) and hydrogen peroxide. Arch Biochem Biophys, 378:269–277. 2000.
Paisan-RuizC, JainS, EvansEW, GilksWP, SimonJ, van der BrugM, Lopez de MunainA, AparicioS, GilAM, KhanN, JohnsonJ, MartinezJR, NichollD, CarreraIM, PenaAS, de SilvaR, LeesA, Marti-MassoJF, Perez-TurJ, WoodNW, SingletonAB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron, 44:595–600. 2004.
183.
PaleologouKE, IrvineGB, El-AgnafOM. Alpha-synuclein aggregation in neurodegenerative diseases and its inhibition as a potential therapeutic strategy. Biochem Soc Trans, 33:1106–1110. 2005.
184.
PargellisC, TongL, ChurchillL, CirilloPF, GilmoreT, GrahamAG, GrobPM, HickeyER, MossN, PavS, ReganJ. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol, 9:268–272. 2002.
185.
ParkJY, LansburyPTJr.Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease. Biochemistry, 42:3696–3700. 2003.
186.
ParkSM, JungHY, KimTD, ParkJH, YangCH, KimJ. Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of alpha-synuclein, a molecular chaperone. J Biol Chem, 277:28512–28520. 2002.
187.
PerrinRJ, WoodsWS, ClaytonDF, GeorgeJM. Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem, 276:41958–41962. 2001.
188.
PesahY, BurgessH, MiddlebrooksB, RonningenK, ProsserJ, TirunagaruV, ZyskJ, MardonG. Whole-mount analysis reveals normal numbers of dopaminergic neurons following misexpression of alpha-synuclein in Drosophila. Genesis, 41:154–159. 2005.
189.
PetitA, KawaraiT, PaitelE, SanjoN, MajM, ScheidM, ChenF, GuY, HasegawaH, Salehi-RadS, WangL, RogaevaE, FraserP, RobinsonB, St George-HyslopP, TandonA. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem, 280:34025–34032. 2005.
190.
PetrucelliL, O'FarrellC, LockhartPJ, BaptistaM, KehoeK, VinkL, ChoiP, WolozinB, FarrerM, HardyJ, CooksonMR. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron, 36:1007–1019. 2002.
191.
PolymeropoulosMH, LavedanC, LeroyE, IdeSE, DehejiaA, DutraA, PikeB, RootH, RubensteinJ, BoyerR, StenroosES, ChandrasekharappaS, AthanassiadouA, PapapetropoulosT, JohnsonWG, LazzariniAM, DuvoisinRC, Di IorioG, GolbeLI, NussbaumRL. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science, 276:2045–2047. 1997.
192.
PountneyDL, TreweekTM, ChatawayT, HuangY, CheginiF, BlumbergsPC, RafteryMJ, GaiWP. Alpha B-crystallin is a major component of glial cytoplasmic inclusions in multiple system atrophy. Neurotox Res, 7:77–85. 2005.
193.
PrzedborskiS, TieuK, PerierC, VilaM. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J Bioenerg Biomembr, 36:375–379. 2004.
194.
PrzedborskiS, VilaM. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. Ann N Y Acad Sci, 991:189–198. 2003.
195.
QianL, BlockML, WeiSJ, LinCF, ReeceJ, PangH, WilsonB, HongJS, FloodPM. Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. J Pharmacol Exp Ther, 319:44–52. 2006.
196.
QuiltyMC, GaiWP, PountneyDL, WestAK, VickersJC. Localization of alpha-, beta-, and gamma-synuclein during neuronal development and alterations associated with the neuronal response to axonal trauma. Exp Neurol, 182:195–207. 2003.
197.
QureshiGA, QureshiAA, MemonSA, ParvezSH. Impact of selenium, iron, copper and zinc in on/off Parkinson's patients on L-dopa therapy. J Neural Transm Suppl, 71:229–236. 2006.
198.
Ralay RanaivoH, CraftJM, HuW, GuoL, WingLK, Van EldikLJ, WattersonDM. Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci, 26:662–670. 2006.
199.
RamakrishnanM, JensenPH, MarshD. Alpha-synuclein association with phosphatidylglycerol probed by lipid spin labels. Biochemistry, 42:12919–12926. 2003.
200.
Rathke-HartliebS, KahlePJ, NeumannM, OzmenL, HaidS, OkochiM, HaassC, SchulzJB. Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice. J Neurochem, 77:1181–1184. 2001.
201.
RichardsonJR, CaudleWM, GuillotTS, WatsonJL, Nakamaru-OgisoE, SeoBB, ShererTB, GreenamyreJT, YagiT, Matsuno-YagiA, MillerGW. Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)Toxicol Sci, 95:196–204. 2007.
202.
RobertsonDC, SchmidtO, NinkinaN, JonesPA, SharkeyJ, BuchmanVL. Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. J Neurochem, 89:1126–1136. 2004.
203.
RottR, SzargelR, HaskinJ, ShaniV, ShainskayaA, ManovI, LianiE, AvrahamE, EngelenderS. Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J Biol Chem, 283:3316–3328. 2008.
204.
Sakaguchi-NakashimaA, MeirJY, JinY, MatsumotoK, HisamotoN. LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr Biol, 17:592–598. 2007.
205.
SapruMK, YatesJW, HoganS, JiangL, HalterJ, BohnMC. Silencing of human alpha-synuclein in vitro and in rat brain using lentiviral-mediated RNAi. Exp Neurol, 198:382–390. 2006.
206.
SchapiraAH, HartleyA, CleeterMW, CooperJM. Free radicals and mitochondrial dysfunction in Parkinson's disease. Biochem Soc Trans, 21:367–370. 1993.
207.
ScherzerCR, GrassJA, LiaoZ, PepivaniI, ZhengB, EklundAC, NeyPA, NgJ, McGoldrickM, MollenhauerB, BresnickEH, SchlossmacherMG. GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. Proc Natl Acad Sci U S A, 105:10907–10912. 2008.
SeniorSL, NinkinaN, DeaconR, BannermanD, BuchmanVL, CraggSJ, Wade-MartinsR. Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. Eur J Neurosci, 27:947–957. 2008.
210.
SevleverD, JiangP, YenSH. Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry, 47:9678–9687. 2008.
211.
SharonR, GoldbergMS, Bar-JosefI, BetenskyRA, ShenJ, SelkoeDJ. alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc Natl Acad Sci U S A, 98:9110–9115. 2001.
212.
ShashidharanP, GoodPF, HsuA, PerlDP, BrinMF, OlanowCW. TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease. Brain Res, 877:379–381. 2000.
213.
ShashidharanP, KramerBC, WalkerRH, OlanowCW, BrinMF. Immunohistochemical localization and distribution of torsinA in normal human and rat brain. Brain Res, 853:197–206. 2000.
214.
Simon-SanchezJ, Herranz-PerezV, Olucha-BordonauF, Perez-TurJ. LRRK2 is expressed in areas affected by Parkinson's disease in the adult mouse brain. Eur J Neurosci, 23:659–666. 2006.
215.
SingletonA, MyersA, HardyJ. The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum Mol Genet, 13:R123–126. 2004.
SmithWW, PeiZ, JiangH, MooreDJ, LiangY, WestAB, DawsonVL, DawsonTM, RossCA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A, 102:18676–18681. 2005.
220.
SoficE, RiedererP, HeinsenH, BeckmannH, ReynoldsGP, HebenstreitG, YoudimMB. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm, 74:199–205. 1988.
221.
SouzaJM, GiassonBI, ChenQ, LeeVM, IschiropoulosH. Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers: implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem, 275:18344–18349. 2000.
222.
SpillantiniMG, CrowtherRA, JakesR, CairnsNJ, LantosPL, GoedertM. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett, 251:205–208. 1998.
223.
SpillantiniMG, CrowtherRA, JakesR, HasegawaM, GoedertM. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A, 95:6469–6473. 1998.
SriramK, MillerDB, O'CallaghanJP. Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem, 96:706–718. 2006.
226.
SriramSR, LiX, KoHS, ChungKK, WongE, LimKL, DawsonVL, DawsonTM. Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin. Hum Mol Genet, 14:2571–2586. 2005.
227.
St MartinJL, KluckenJ, OuteiroTF, NguyenP, Keller-McGandyC, Cantuti-CastelvetriI, GrammatopoulosTN, StandaertDG, HymanBT, McLeanPJ. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. J Neurochem, 100:1449–1457. 2007.
228.
StefanisL, LarsenKE, RideoutHJ, SulzerD, GreeneLA. Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci, 21:9549–9560. 2001.
229.
Sturchler-PierratC, AbramowskiD, DukeM, WiederholdKH, MistlC, RothacherS, LedermannB, BurkiK, FreyP, PaganettiPA, WaridelC, CalhounME, JuckerM, ProbstA, StaufenbielM, SommerB. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A, 94:13287–13292. 1997.
230.
SurmeierDJ. Calcium, ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol, 6:933–938. 2007.
231.
TakeuchiH, JinS, WangJ, ZhangG, KawanokuchiJ, KunoR, SonobeY, MizunoT, SuzumuraA. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem, 281:21362–21368. 2006.
232.
TanEK, ZhaoY, SkipperL, TanMG, Di FonzoA, SunL, Fook-ChongS, TangS, ChuaE, YuenY, TanL, PavanniR, WongMC, KolatkarP, LuCS, BonifatiV, LiuJJ. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet, 120:857–863. 2007.
233.
TaymansJM, Van den HauteC, BaekelandtV. Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem, 98:951–961. 2006.
234.
TripanichkulW, SripanichkulchaiK, FinkelsteinDI. Estrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Brain Res, 1084:28–37. 2006.
235.
TruongDD, BhidayasiriR, WoltersE. Management of non-motor symptoms in advanced Parkinson disease. J Neurol Sci, 266:216–228. 2008.
236.
UedaK, FukushimaH, MasliahE, XiaY, IwaiA, YoshimotoM, OteroDA, KondoJ, IharaY, SaitohT. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A, 90:11282–11286. 1993.
237.
UngerEL, EveDJ, PerezXA, ReichenbachDK, XuY, LeeMK, AndrewsAM. Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice. Neurobiol Dis, 21:431–443. 2006.
238.
UverskyVN. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem, 103:17–37. 2007.
239.
UverskyVN. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res, 318:225–241. 2004.
240.
UverskyVN, LiJ, FinkAL. Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem, 276:10737–10744. 2001.
241.
UverskyVN, LiJ, SouillacP, MillettIS, DoniachS, JakesR, GoedertM, FinkAL. Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem, 277:11970–11978. 2002.
242.
UverskyVN, YaminG, SouillacPO, GoersJ, GlaserCB, FinkAL. Methionine oxidation inhibits fibrillation of human alpha-synuclein in vitro. FEBS Lett, 517:239–244. 2002.
van der PuttenH, WiederholdKH, ProbstA, BarbieriS, MistlC, DannerS, KauffmannS, HofeleK, SpoorenWP, RueggMA, LinS, CaroniP, SommerB, TolnayM, BilbeG. Neuropathology in mice expressing human alpha-synuclein. J Neurosci, 20:6021–6029. 2000.
245.
van EgmondWN, KortholtA, PlakK, BosgraafL, BosgraafS, Keizer-GunninkI, van HaastertPJ. Intramolecular activation mechanism of the dictyostelium LRRK2-homolog Roco protein GbpC. J Biol Chem, 283:30412–30420. 2008.
246.
van HamTJ, ThijssenKL, BreitlingR, HofstraRM, PlasterkRH, NollenEA. C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genet, 4:e1000027. 2008.
247.
VanacoreN, NappoA, GentileM, BrustolinA, PalangeS, LiberatiA, Di RezzeS, CaldoraG, GaspariniM, BenedettiF, BonifatiV, ForastiereF, QuerciaA, MecoG. Evaluation of risk of Parkinson's disease in a cohort of licensed pesticide users. Neurol Sci, 23,suppl 2:S119–S120. 2002.
248.
VartiainenS, AarnioV, LaksoM, WongG. Increased lifespan in transgenic Caenorhabditis elegans overexpressing human alpha-synuclein. Exp Gerontol, 41:871–876. 2006.
249.
VartiainenS, PehkonenP, LaksoM, NassR, WongG. Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. Neurobiol Dis, 22:477–486. 2006.
250.
VirmaniA, GaetaniF, BiniendaZ, XuA, DuhartH, AliSF. Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine. Ann N Y Acad Sci, 1025:267–273. 2004.
251.
VulpettiA, BosottiR. Sequence and structural analysis of kinase ATP pocket residues. Farmaco, 59:759–765. 2004.
252.
WahnerAD, BronsteinJM, BordelonYM, RitzB. Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology, 69:1836–1842. 2007.
253.
WakabayashiK, HayashiS, KakitaA, YamadaM, ToyoshimaY, YoshimotoM, TakahashiH. Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol, 96:445–452. 1998.
254.
WalkerRH, BrinMF, SanduD, GujjariP, HofPR, Warren OlanowC, ShashidharanP. Distribution and immunohistochemical characterization of torsinA immunoreactivity in rat brain. Brain Res, 900:348–354. 2001.
255.
WangC, TanJM, HoMW, ZaidenN, WongSH, ChewCL, EngPW, LimTM, DawsonTM, LimKL. Alterations in the solubility and intracellular localization of parkin by several familial Parkinson's disease-linked point mutations. J Neurochem, 93:422–431. 2005.
256.
WangD, TangB, ZhaoG, PanQ, XiaK, BodmerR, ZhangZ. Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Mol Neurodegener, 3:3. 2008.
257.
WangYM, PuP, LeWD. ATP depletion is the major cause of MPP+ induced dopamine neuronal death and worm lethality in alpha-synuclein transgenic C. elegans. Neurosci Bull, 23:329–335. 2007.
258.
WeinrebPH, ZhenW, PoonAW, ConwayKA, LansburyPTJr.NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry, 35:13709–13715. 1996.
259.
WestA, PeriquetM, LincolnS, LuckingCB, NichollD, BonifatiV, RawalN, GasserT, LohmannE, DeleuzeJF, MaraganoreD, LeveyA, WoodN, DurrA, HardyJ, BriceA, FarrerM. Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet, 114:584–591. 2002.
260.
WestAB, MooreDJ, BiskupS, BugayenkoA, SmithWW, RossCA, DawsonVL, DawsonTM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A, 102:16842–16847. 2005.
261.
WestAB, MooreDJ, ChoiC, AndrabiSA, LiX, DikemanD, BiskupS, ZhangZ, LimKL, DawsonVL, DawsonTM. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet, 16:223–232. 2007.
262.
WesterlundM, BelinAC, AnvretA, BickfordP, OlsonL, GalterD. Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: implications for Parkinson's disease. Neuroscience, 152:429–436. 2008.
263.
WiessnerC, AllegriniPR, RupallaK, SauerD, OltersdorfT, McGregorAL, BischoffS, BottigerBW, van der PuttenH. Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci Lett, 268:119–122. 1999.
264.
WindischM, WolfH, Hutter-PaierB, WronskiR. The role of alpha-synuclein in neurodegenerative diseases: a potential target for new treatment strategies?Neurodegener Dis, 5:218–221. 2008.
WrightJA, BrownDR. Alpha-synuclein and its role in metal binding: relevance to Parkinson's disease. J Neurosci Res, 86:496–503. 2008.
267.
XuZ, MaroneyAC, DobrzanskiP, KukekovNV, GreeneLA. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol, 21:4713–4724. 2001.
268.
YamadaM, MizunoY, MochizukiH. Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease. Hum Gene Ther, 16:262–270. 2005.
269.
YaminG, GlaserCB, UverskyVN, FinkAL. Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J Biol Chem, 278:27630–27635. 2003.
270.
YoungAJ, JohnsonS, SteffensDC, DoraiswamyPM. Coenzyme Q10: a review of its promise as a neuroprotectant. CNS Spectrum, 12:62–68. 2007.
271.
YuF, XuH, ZhuoM, SunL, DongA, LiuX. Impairment of redox state and dopamine level induced by alpha-synuclein aggregation and the prevention effect of hsp70. Biochem Biophys Res Commun, 331:278–284. 2005.
272.
ZarranzJJ, AlegreJ, Gomez-EstebanJC, LezcanoE, RosR, AmpueroI, VidalL, HoenickaJ, RodriguezO, AtaresB, LlorensV, Gomez TortosaE, del SerT, MunozDG, de YebenesJG. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol, 55:164–173. 2004.
273.
ZengBY, IravaniMM, LinST, IrifuneM, KuoppamakiM, Al-BarghouthyG, SmithL, JacksonMJ, RoseS, MedhurstAD, JennerP. MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome. Eur J Neurosci, 23:1766–1774. 2006.
274.
ZhangW, WangT, PeiZ, MillerDS, WuX, BlockML, WilsonB, ZhouY, HongJS, ZhangJ. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J, 19:533–542. 2005.
275.
ZhouW, FreedCR. DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem, 280:43150–43158. 2005.
276.
ZhuM, RajamaniS, KaylorJ, HanS, ZhouF, FinkAL. The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem, 279:26846–26857. 2004.
ZimprichA, Muller-MyhsokB, FarrerM, LeitnerP, SharmaM, HulihanM, LockhartP, StrongoskyA, KachergusJ, CalneDB, StoesslJ, UittiRJ, PfeifferRF, TrenkwalderC, HomannN, OttE, WenzelK, AsmusF, HardyJ, WszolekZ, GasserT. The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval. Am J Hum Genet, 74:11–19. 2004.
