alpha synuclein

Summary

Summary: A synuclein that is a major component of LEWY BODIES that plays a role in neurodegeneration and neuroprotection.

Top Publications

  1. Stefanova N, Hainzer M, Stemberger S, Couillard Despres S, Aigner L, Poewe W, et al. Striatal transplantation for multiple system atrophy--are grafts affected by alpha-synucleinopathy?. Exp Neurol. 2009;219:368-71 pubmed publisher
    ..Our data suggest that the presence of MSA-like alpha-synuclein oligodendrogliopathy and related to it pro-inflammatory microenvironment may compromise the connectivity and neurorestorative outcome of striatal grafts. ..
  2. Cao P, Yuan Y, Pehek E, Moise A, Huang Y, Palczewski K, et al. Alpha-synuclein disrupted dopamine homeostasis leads to dopaminergic neuron degeneration in Caenorhabditis elegans. PLoS ONE. 2010;5:e9312 pubmed publisher
    ..These results provide in vivo evidence supporting a critical role for dopamine homeostasis in supporting dopaminergic neuron integrity. ..
  3. Ferreon A, Gambin Y, Lemke E, Deniz A. Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proc Natl Acad Sci U S A. 2009;106:5645-50 pubmed publisher
  4. Liu W, Vives Bauza C, Acin Perez R, Yamamoto A, Tan Y, Li Y, et al. PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease. PLoS ONE. 2009;4:e4597 pubmed publisher
    ..Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and alpha-synclein aggregation. ..
  5. Cahill C, Lahiri D, Huang X, Rogers J. Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochim Biophys Acta. 2009;1790:615-28 pubmed publisher
    ..More recently a putative IRE-like sequence was hypothesized present in the Parkinsons's alpha synuclein (ASYN) transcript (see [A.L. Friedlich, R.E. Tanzi, J.T...
  6. Seidel K, Schols L, Nuber S, Petrasch Parwez E, Gierga K, Wszolek Z, et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann Neurol. 2010;67:684-9 pubmed publisher
  7. Mak S, McCormack A, Langston J, Kordower J, Di Monte D. Decreased alpha-synuclein expression in the aging mouse substantia nigra. Exp Neurol. 2009;220:359-65 pubmed publisher
  8. Nishioka K, Ross O, Ishii K, Kachergus J, Ishiwata K, Kitagawa M, et al. Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord. 2009;24:1811-9 pubmed publisher
    ..Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment. ..
  9. Nuytemans K, Meeus B, Crosiers D, Brouwers N, Goossens D, Engelborghs S, et al. Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. Hum Mutat. 2009;30:1054-61 pubmed publisher
    ..Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful. ..

More Information

Publications62

  1. Yuan B, Sierks M. Intracellular targeting and clearance of oligomeric alpha-synuclein alleviates toxicity in mammalian cells. Neurosci Lett. 2009;459:16-8 pubmed publisher
    ..Non-traditional intrabody secretion therefore represents an effective method to target and clear a variety of harmful intracellular species. ..
  2. Reynolds A, Stone D, Mosley R, Gendelman H. Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol. 2009;182:4137-49 pubmed publisher
    ..These data support the importance of adaptive immunity in the regulation of Parkinson's disease-associated microglial inflammation. ..
  3. Camargos S, Dornas L, Momeni P, Lees A, Hardy J, Singleton A, et al. Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord. 2009;24:662-6 pubmed publisher
    ..We have demonstrated that EOPD accounts for a high frequency of IPD cases in our tertiary referral center. PRKN was the most commonly mutated gene, but we also identified a novel mutation in PINK1 and a novel variant in LRRK2. ..
  4. Emadi S, Kasturirangan S, Wang M, Schulz P, Sierks M. Detecting morphologically distinct oligomeric forms of alpha-synuclein. J Biol Chem. 2009;284:11048-58 pubmed publisher
  5. Stefanova N, Bücke P, Duerr S, Wenning G. Multiple system atrophy: an update. Lancet Neurol. 2009;8:1172-8 pubmed publisher
    ..Although the trials did not find any positive effects on disease progression, they generated important trial expertise in MSA and were only possible because of the establishment of international networks. ..
  6. Wenning G, Stefanova N. Recent developments in multiple system atrophy. J Neurol. 2009;256:1791-808 pubmed publisher
    ..An outline of the rationale for managing symptomatic deterioration in MSA is provided together with a summary of novel experimental therapeutic approaches to decrease disease progression. ..
  7. Qing H, Wong W, McGeer E, McGeer P. Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun. 2009;387:149-52 pubmed publisher
    Mutations in the alpha synuclein gene (SNCA) are the most potent cause of autosomal dominant Parkinson disease (PD) while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause...
  8. Putcha P, Danzer K, Kranich L, Scott A, Silinski M, Mabbett S, et al. Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity. J Pharmacol Exp Ther. 2010;332:849-57 pubmed publisher
    ..With a low EC(50), brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD. ..
  9. Nemani V, Lu W, Berge V, Nakamura K, Onoa B, Lee M, et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65:66-79 pubmed publisher
    ..Increased levels of alpha-synuclein thus produce a specific, physiological defect in synaptic vesicle recycling that precedes detectable neuropathology. ..
  10. Rospigliosi C, McClendon S, Schmid A, Ramlall T, Barre P, Lashuel H, et al. E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein. J Mol Biol. 2009;388:1022-32 pubmed publisher
  11. Beach T, Adler C, Lue L, Sue L, Bachalakuri J, Henry Watson J, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 2009;117:613-34 pubmed publisher
    ..It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases...
  12. Karpinar D, Balija M, Kügler S, Opazo F, Rezaei Ghaleh N, Wender N, et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. EMBO J. 2009;28:3256-68 pubmed publisher
  13. Lin X, Parisiadou L, Gu X, Wang L, Shim H, Sun L, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron. 2009;64:807-27 pubmed publisher
  14. Lou H, Montoya S, Alerte T, Wang J, Wu J, Peng X, et al. Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. J Biol Chem. 2010;285:17648-61 pubmed publisher
    ..These findings extend our understanding of normal a-Syn biology and have implications for the dopamine dysfunction of Parkinson disease. ..
  15. Riedel M, Goldbaum O, Richter Landsberg C. alpha-Synuclein promotes the recruitment of tau to protein inclusions in oligodendroglial cells: effects of oxidative and proteolytic stress. J Mol Neurosci. 2009;39:226-34 pubmed publisher
    ..The data indicate that oxidatively modified alpha-synuclein is degraded by the proteasome and that it plays a pro-aggregatory role for tau in this cell culture model system. ..
  16. Scholz S, Houlden H, Schulte C, Sharma M, Li A, Berg D, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65:610-4 pubmed publisher
    ..SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 x 10(-12); odds ratio 6.2) [corrected]. ..
  17. McCormack A, Di Monte D. Enhanced alpha-synuclein expression in human neurodegenerative diseases: pathogenetic and therapeutic implications. Curr Protein Pept Sci. 2009;10:476-82 pubmed
    ..g. macroautophagy) involved in alpha-synuclein clearance, and (iii) the development of anti-aggregation agents counteracting the formation of toxic oligomeric or fibrillar forms of the protein. ..
  18. Chu Y, Dodiya H, Aebischer P, Olanow C, Kordower J. Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions. Neurobiol Dis. 2009;35:385-98 pubmed publisher
  19. Desplats P, Lee H, Bae E, Patrick C, Rockenstein E, Crews L, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009;106:13010-5 pubmed publisher
    ..These findings demonstrate the cell-to-cell transmission of alpha-synuclein aggregates and provide critical insights into the mechanism of pathological progression in PD and other proteinopathies. ..
  20. Schwach G, Tschemmernegg M, Pfragner R, Ingolic E, Schreiner E, Windisch M. Establishment of stably transfected rat neuronal cell lines expressing alpha-synuclein GFP fusion proteins. J Mol Neurosci. 2010;41:80-8 pubmed publisher
    ..Taken together, these results suggest that abnormal accumulation of alpha-synuclein could lead to mitochondrial alterations that might result in oxidative stress and eventually, cell death. ..
  21. Yu W, Dorado B, Figueroa H, Wang L, Planel E, Cookson M, et al. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol. 2009;175:736-47 pubmed publisher
    ..This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade alpha-syn aggregates. ..
  22. Gu X, Long C, Sun L, Xie C, Lin X, Cai H. Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain. 2010;3:12 pubmed publisher
  23. Zhong S, Luo X, Chen X, Cai Q, Liu J, Chen X, et al. Expression and subcellular location of alpha-synuclein during mouse-embryonic development. Cell Mol Neurobiol. 2010;30:469-82 pubmed publisher
    ..The nuclear location of alpha-SYN may hint at an important function in these events. ..
  24. Hardy J, Lewis P, Revesz T, Lees A, Paisan Ruiz C. The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev. 2009;19:254-65 pubmed publisher
  25. Lee H, Suk J, Patrick C, Bae E, Cho J, Rho S, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010;285:9262-72 pubmed publisher
    ..This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target. ..
  26. Frost B, Diamond M. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11:155-9 pubmed publisher
    ..If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain. ..
  27. Chau K, Ching H, Schapira A, Cooper J. Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson's disease pathogenesis. J Neurochem. 2009;110:1005-13 pubmed publisher
    b>Alpha synuclein can be phosphorylated at serine129 (P-S129), and the presence of highly phosphorylated alpha-synuclein in Lewy bodies suggests changes to its phosphorylation status has an important pathological role...
  28. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci. 2009;29:13578-88 pubmed publisher
    ..Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD. ..
  29. Kim S, Cho S, Kim K, Shin K, Kim H, Park C, et al. Alpha-synuclein induces migration of BV-2 microglial cells by up-regulation of CD44 and MT1-MMP. J Neurochem. 2009;109:1483-96 pubmed publisher
    ..With the recruitment of the microglial population into the SNpc during dopaminergic neurodegeneration, alpha-synuclein may play a role in accelerating the pathogenesis of PD. ..
  30. Devi L, Anandatheerthavarada H. Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer's and Parkinson's diseases. Biochim Biophys Acta. 2010;1802:11-9 pubmed publisher
    ..accumulation of proteins such as plasma membrane associated amyloid precursor protein (APP) and cytosolic alpha synuclein in the pathogenesis of mitochondrial dysfunction in Alzheimer's disease (AD) and Parkinson's disease (PD), ..
  31. Luk K, Song C, O BRIEN P, Stieber A, Branch J, Brunden K, et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051-6 pubmed publisher
  32. Al Chalabi A, Dürr A, Wood N, Parkinson M, Camuzat A, Hulot J, et al. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS ONE. 2009;4:e7114 pubmed publisher
    ..035). We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. ClinicalTrials.gov NCT00211224. ..
  33. Kim H, Cho M, Kumar A, Maier E, Siebenhaar C, Becker S, et al. Structural properties of pore-forming oligomers of alpha-synuclein. J Am Chem Soc. 2009;131:17482-9 pubmed publisher
    ..The oligomers form ion channels with well-defined conductance states in a variety of membranes, and their beta-structure differs from that of amyloid fibrils of alpha-synuclein. ..
  34. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet. 2009;41:1303-7 pubmed publisher
    ..Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD. ..
  35. Bodner C, Dobson C, Bax A. Multiple tight phospholipid-binding modes of alpha-synuclein revealed by solution NMR spectroscopy. J Mol Biol. 2009;390:775-90 pubmed publisher
    ..The NMR data appear incompatible with the commonly assumed model where alphaS lies in an alpha-helical conformation on the membrane surface and instead suggest that considerable remodeling of the vesicles is induced by alphaS. ..
  36. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE. 2009;4:e5515 pubmed publisher
    ..Furthermore, macroautophagy induction in the context of ASYN over-expression, in contrast to other settings, appears to be a detrimental response, leading to neuronal death. ..
  37. Mosharov E, Larsen K, Kanter E, Phillips K, Wilson K, Schmitz Y, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron. 2009;62:218-29 pubmed publisher
    ..Thus, an interaction between Ca2+, DA(cyt), and alpha-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets. ..
  38. Chung C, Koprich J, Siddiqi H, Isacson O. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci. 2009;29:3365-73 pubmed publisher
    ..These findings can provide ideas for antecedent biomarkers and presymptomatic interventions in PD. ..
  39. Mak S, McCormack A, Manning Bog A, Cuervo A, Di Monte D. Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem. 2010;285:13621-9 pubmed publisher
    ..It is conceivable that these neuronal mechanisms of protein clearance play an important role in neurodegenerative processes characterized by abnormal alpha-synuclein buildup. ..
  40. Ross O, Gosal D, Stone J, Lincoln S, Heckman M, Irvine G, et al. Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson's disease. Mech Ageing Dev. 2007;128:378-82 pubmed
    ..It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD. ..
  41. Al Wandi A, Ninkina N, Millership S, Williamson S, Jones P, Buchman V. Absence of alpha-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiol Aging. 2010;31:796-804 pubmed publisher
  42. Fountaine T, Venda L, Warrick N, Christian H, Brundin P, Channon K, et al. The effect of alpha-synuclein knockdown on MPP+ toxicity in models of human neurons. Eur J Neurosci. 2008;28:2459-73 pubmed publisher
  43. Theodore S, Cao S, McLean P, Standaert D. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol. 2008;67:1149-58 pubmed publisher
    ..These data show that overexpression of alpha-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity. ..
  44. Waxman E, Giasson B. Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta. 2009;1792:616-24 pubmed publisher
    ..In this review, some of the evidence for the different mechanisms of alpha-synuclein toxicity is presented and discussed. ..
  45. Georgieva E, Ramlall T, Borbat P, Freed J, Eliezer D. Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles. J Am Chem Soc. 2008;130:12856-7 pubmed publisher
  46. Perry G, Zhu X, Babar A, Siedlak S, Yang Q, Ito G, et al. Leucine-rich repeat kinase 2 colocalizes with alpha-synuclein in Parkinson's disease, but not tau-containing deposits in tauopathies. Neurodegener Dis. 2008;5:222-4 pubmed publisher
    ..Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of Parkinson's disease and related disorders. ..
  47. Moussa C, Mahmoodian F, Tomita Y, Sidhu A. Dopamine differentially induces aggregation of A53T mutant and wild type alpha-synuclein: insights into the protein chemistry of Parkinson's disease. Biochem Biophys Res Commun. 2008;365:833-9 pubmed
    ..The present data indicate that mutation in the alpha-synuclein gene may predispose the protein to dopamine-induced aggregation, thereby contributing to disease pathogenesis. ..
  48. Burke W, Kumar V, Pandey N, Panneton W, Gan Q, Franko M, et al. Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol. 2008;115:193-203 pubmed
    ..Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD. ..
  49. Fountaine T, Wade Martins R. RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res. 2007;85:351-63 pubmed
  50. Song Y, Halliday G, Holton J, Lashley T, O Sullivan S, McCann H, et al. Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol. 2009;68:1073-83 pubmed publisher
    ..These heterogeneous astroglial responses in PD, MSA, PSP, and CBD indicate distinct underlying pathogenic mechanisms in each disorder. ..
  51. Gasser T. Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med. 2009;11:e22 pubmed publisher
    ..These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms. ..
  52. Gerard M, Deleersnijder A, Daniëls V, Schreurs S, Munck S, Reumers V, et al. Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology. J Neurosci. 2010;30:2454-63 pubmed publisher
    ..Our data explain previously described neuroregenerative and neuroprotective effects of immunophilin ligands and validate FKBPs as a novel drug target for the causative treatment of PD. ..
  53. Lewandowski N, Ju S, Verbitsky M, Ross B, Geddie M, Rockenstein E, et al. Polyamine pathway contributes to the pathogenesis of Parkinson disease. Proc Natl Acad Sci U S A. 2010;107:16970-5 pubmed publisher
    ..Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis. ..