synucleins

Summary

Summary: A family of homologous proteins of low MOLECULAR WEIGHT that are predominately expressed in the BRAIN and that have been implicated in a variety of human diseases. They were originally isolated from CHOLINERGIC FIBERS of TORPEDO.

Top Publications

  1. Chen L, Feany M. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci. 2005;8:657-63 pubmed
    ..Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity. ..
  2. Chung K, Thomas B, Li X, Pletnikova O, Troncoso J, Marsh L, et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science. 2004;304:1328-31 pubmed
    ..The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates. ..
  3. Von Bohlen Und Halbach O. Synucleins and their relationship to Parkinson's disease. Cell Tissue Res. 2004;318:163-74 pubmed
    ..Indeed, even the normal cellular functions of alpha-synuclein and of the other synucleins (beta-synuclein and gamma-synuclein) are still unknown...
  4. Li W, Hoffman P, Stirling W, Price D, Lee M. Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations. J Neurochem. 2004;88:401-10 pubmed
    ..Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing alpha-Syn is a likely contributor to axonal aggregation of alpha-Syn in alpha-synucleinopathy. ..
  5. Singleton A, Gwinn Hardy K. Parkinson's disease and dementia with Lewy bodies: a difference in dose?. Lancet. 2004;364:1105-7 pubmed
  6. Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H. Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson's disease. J Neurochem. 2004;91:451-61 pubmed
  7. Miller D, Hague S, Clarimon J, Baptista M, Gwinn Hardy K, Cookson M, et al. Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology. 2004;62:1835-8 pubmed
    ..However, at the protein level in brain, there was a greater effect on deposition of aggregated forms into insoluble fractions than on net expression of soluble alpha-synuclein. ..
  8. Suzuki K, Iseki E, Togo T, Yamaguchi A, Katsuse O, Katsuyama K, et al. Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses. Acta Neuropathol. 2007;114:481-9 pubmed
    ..We have previously reported neuronal accumulation of both alpha- and beta-synucleins in brain tissue of a GM2 gangliosidosis mouse model...
  9. Oaks A, Sidhu A. Synuclein modulation of monoamine transporters. FEBS Lett. 2011;585:1001-6 pubmed publisher
    ..Emerging data indicate a role for synucleins in monoamine neurotransmitter homeostasis...

More Information

Publications62

  1. Walsh D, Selkoe D. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett. 2004;11:213-28 pubmed
    ..With particular reference to AD and PD, we review recent evidence that soluble oligomers are the principal pathogenic species that drive neuronal dysfunction. ..
  2. Wang Y, Takeda A, Osaka H, Hara Y, Furuta A, Setsuie R, et al. Accumulation of beta- and gamma-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse. Brain Res. 2004;1019:1-9 pubmed
    ..In the present study, we used immunohistochemistry to demonstrate accelerated accumulation of beta- and gamma-synucleins in axonal spheroids in gracile axonal dystrophy (gad) mice, which do not express ubiquitin carboxyl-terminal ..
  3. Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, et al. Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology. 2004;63:805-11 pubmed
    ..Mutations in the beta-synuclein gene may predispose to DLB. ..
  4. Ibanez P, Bonnet A, Débarges B, Lohmann E, Tison F, Pollak P, et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet. 2004;364:1169-71 pubmed
    ..These results indicate that SNCA is more frequently associated with familial Parkinson's disease than previously thought, and that there is a clear dosage effect according to the number of supernumerary copies of this gene. ..
  5. Wszolek Z, Pfeiffer R, Tsuboi Y, Uitti R, McComb R, Stoessl A, et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology. 2004;62:1619-22 pubmed
    ..Genetic studies suggested linkage to the PARK8 locus on chromosome 12. ..
  6. Rochet J, Outeiro T, Conway K, Ding T, Volles M, Lashuel H, et al. Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease. J Mol Neurosci. 2004;23:23-34 pubmed
    ..These variants might be useful to test whether membrane binding by alpha-synuclein is necessary for neurodegeneration in transgenic animal models of PD. ..
  7. Olanow C, Perl D, Demartino G, McNaught K. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 2004;3:496-503 pubmed
    ..The concept of Lewy bodies as aggresome-related inclusions fits well with ongoing discoveries suggesting that altered protein handling might contribute to the neurodegenerative process in familial and sporadic forms of PD. ..
  8. Cuervo A, Stefanis L, Fredenburg R, Lansbury P, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292-5 pubmed
    ..These findings may underlie the toxic gain-of-function by the mutants. ..
  9. Snyder H, Mensah K, Hsu C, Hashimoto M, Surgucheva I, Festoff B, et al. beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein. J Biol Chem. 2005;280:7562-9 pubmed
    ..Monomeric alpha- and beta-synucleins inhibited the 20 S and 26 S proteasomal activities only weakly, but monomeric gamma-synuclein strongly inhibited ..
  10. Mishizen Eberz A, Norris E, Giasson B, Hodara R, Ischiropoulos H, Lee V, et al. Cleavage of alpha-synuclein by calpain: potential role in degradation of fibrillized and nitrated species of alpha-synuclein. Biochemistry. 2005;44:7818-29 pubmed
    ..These results provide insight into possible disease mechanisms underlying synucleinopathies since the formation of alpha-syn fibrils could be causally linked to the onset/progression of these disorders. ..
  11. Singleton A. Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin. Trends Neurosci. 2005;28:416-21 pubmed
    ..In addition, it will discuss the recent identification of LRRK2 mutation as a cause of PD and the potential of this finding to provide further insight into disease. ..
  12. Wersinger C, Vernier P, Sidhu A. Trypsin disrupts the trafficking of the human dopamine transporter by alpha-synuclein and its A30P mutant. Biochemistry. 2004;43:1242-53 pubmed
    ..These results show that alpha-synuclein modulates hDAT function through trafficking of the transporter in a process that can be disrupted by trypsin. ..
  13. Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. 2004;2:e362 pubmed
    ..We further demonstrate that DJ-1 chaperone activity in vivo extends to alpha-synuclein, a protein implicated in PD pathogenesis. ..
  14. Zarranz J, Alegre J, Gómez Esteban J, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55:164-73 pubmed
    ..Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein. ..
  15. Chandra S, Fornai F, Kwon H, Yazdani U, Atasoy D, Liu X, et al. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A. 2004;101:14966-71 pubmed
    ..To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack alpha- and/or beta-..
  16. Lo Bianco C, Schneider B, Bauer M, Sajadi A, Brice A, Iwatsubo T, et al. 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. 2004;101:17510-5 pubmed
    ..These results indicate that parkin gene therapy may represent a promising candidate treatment for PD. ..
  17. Crews L, Tsigelny I, Hashimoto M, Masliah E. Role of synucleins in Alzheimer's disease. Neurotox Res. 2009;16:306-17 pubmed publisher
    ..Thus, better understanding the steps involved in the process of Abeta and alpha-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD. ..
  18. Li W, West N, Colla E, Pletnikova O, Troncoso J, Marsh L, et al. Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc Natl Acad Sci U S A. 2005;102:2162-7 pubmed
    ..Collectively, our results indicate that the biology behind the generation and accumulation of alpha-SynDeltaC is likely to have relevance for the initiation and the progression of alpha-Syn aggregation in vivo. ..
  19. Lim K, Chew K, Tan J, Wang C, Chung K, Zhang Y, et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci. 2005;25:2002-9 pubmed
    ..Our results suggest that parkin is a dual-function ubiquitin ligase and that K63-linked ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with PD. ..
  20. Papachroni K, Ninkina N, Wanless J, Kalofoutis A, Gnuchev N, Buchman V. Peripheral sensory neurons survive in the absence of alpha- and gamma-synucleins. J Mol Neurosci. 2005;25:157-64 pubmed
    ..It has been suggested that synucleins are involved in intracellular processes associated with survival of neurons and their response to stress, and ..
  21. Surguchov A. Molecular and cellular biology of synucleins. Int Rev Cell Mol Biol. 2008;270:225-317 pubmed publisher
    b>Synucleins are small, soluble proteins expressed primarily in neural tissues and certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein...
  22. Greten Harrison B, Polydoro M, Morimoto Tomita M, Diao L, Williams A, Nie E, et al. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci U S A. 2010;107:19573-8 pubmed publisher
    b>Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein...
  23. Surguchov A. Synucleins: are they two-edged swords?. J Neurosci Res. 2013;91:161-6 pubmed publisher
    ..Numerous data demonstrate that synucleins are implicated in two groups of the most devastating human disorders, i.e...
  24. Fortin D, Troyer M, Nakamura K, Kubo S, Anthony M, Edwards R. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 2004;24:6715-23 pubmed
  25. Greenamyre J, Hastings T. Biomedicine. Parkinson's--divergent causes, convergent mechanisms. Science. 2004;304:1120-2 pubmed
  26. Jao C, Der Sarkissian A, Chen J, Langen R. Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling. Proc Natl Acad Sci U S A. 2004;101:8331-6 pubmed
    ..Similar helical structures could also apply to apolipoproteins and other lipid-interacting proteins with related 11-aa repeats. ..
  27. Yavich L, Tanila H, Vepsäläinen S, Jakala P. Role of alpha-synuclein in presynaptic dopamine recruitment. J Neurosci. 2004;24:11165-70 pubmed
    ..Reducing capacity of the storage pool in transgenic A30P mice led to paradoxical effects of l-dopa, which elevated dopamine release in response to single stimulation but decreased the refilling rate of the RRP. ..
  28. Fernagut P, Chesselet M. Alpha-synuclein and transgenic mouse models. Neurobiol Dis. 2004;17:123-30 pubmed
    ..This review describes the different alpha-synuclein transgenic models, their clinical relevance to synucleinopathies, and their further utilization to understand the disease process. ..
  29. Fleming S, Salcedo J, Fernagut P, Rockenstein E, Masliah E, Levine M, et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci. 2004;24:9434-40 pubmed
    ..These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies. ..
  30. Salem S, Allsop D, Mann D, Tokuda T, El Agnaf O. An investigation into the lipid-binding properties of alpha-, beta- and gamma-synucleins in human brain and cerebrospinal fluid. Brain Res. 2007;1170:103-11 pubmed
    ..Our data confirm the fatty acid binding properties of alpha-syn, and to a lesser extent beta-syn, but suggest that gamma-syn does not share this same characteristic. ..
  31. Pletnikova O, West N, Lee M, Rudow G, Skolasky R, Dawson T, et al. Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging. 2005;26:1183-92 pubmed
    ..This suggests that Abeta enhances the development of cortical alpha-synuclein lesions in cases of PD. ..
  32. Kubo S, Nemani V, Chalkley R, Anthony M, Hattori N, Mizuno Y, et al. A combinatorial code for the interaction of alpha-synuclein with membranes. J Biol Chem. 2005;280:31664-72 pubmed
  33. Haywood A, Staveley B. Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 2004;5:14 pubmed
    ..If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress alpha-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD. ..
  34. Mishizen Eberz A, Guttmann R, Giasson B, Day G, Hodara R, Ischiropoulos H, et al. Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J Neurochem. 2003;86:836-47 pubmed
    ..Elucidating the role of calpain I in the proteolytic processing of alpha-syn in normal and diseased brains may clarify mechanisms of neurodegenerative alpha-synucleinopathies. ..
  35. Wersinger C, Prou D, Vernier P, Niznik H, Sidhu A. Mutations in the lipid-binding domain of alpha-synuclein confer overlapping, yet distinct, functional properties in the regulation of dopamine transporter activity. Mol Cell Neurosci. 2003;24:91-105 pubmed
  36. Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromolecular Med. 2003;4:21-36 pubmed
    ..New evidence may also provide a rationale for the mitochondrial membrane as a target for therapy in a variety of neurodegenerative diseases. ..
  37. Oluwatosin Chigbu Y, Robbins A, Scott C, Arriza J, Reid J, Zysk J. Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. Biochem Biophys Res Commun. 2003;309:679-84 pubmed
    ..These data, consistent with a protective role for parkin, extend previous findings to include a functional association between parkin and the wt form of alphaS. ..
  38. Hashimoto M, Rockenstein E, Masliah E. Transgenic models of alpha-synuclein pathology: past, present, and future. Ann N Y Acad Sci. 2003;991:171-88 pubmed
  39. Zhu M, Li J, Fink A. The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation. J Biol Chem. 2003;278:40186-97 pubmed
    ..Protofibrillar or fibrillar alpha-synuclein caused a much more rapid destruction of the membrane than soluble monomeric alpha-synuclein, indicating that protofibrils (oligomers) or fibrils are likely to be significantly neurotoxic. ..
  40. Gómez Santos C, Ferrer I, Santidrian A, Barrachina M, Gil J, Ambrosio S. Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res. 2003;73:341-50 pubmed
    ..The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration. ..
  41. Tofaris G, Razzaq A, Ghetti B, Lilley K, Spillantini M. Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem. 2003;278:44405-11 pubmed
    ..Accordingly, carboxyl-terminal-truncated alpha-synuclein, presumably the result of aberrant proteolysis, is found only in association with alpha-synuclein aggregates. ..
  42. Lee S, Kim S, Kim I, Ko J, Jeong C, Kim G, et al. Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. J Biol Chem. 2003;278:44552-9 pubmed publisher
    ..On the basis of the chaperone activity the possible role of DJ-1 in the pathogenesis of Parkinson's disease is discussed...
  43. Volles M, Lansbury P. Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry. 2003;42:7871-8 pubmed
    ..Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed. ..
  44. Wersinger C, Prou D, Vernier P, Sidhu A. Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress. FASEB J. 2003;17:2151-3 pubmed
    ..These studies suggest a novel normative role for alpha-synuclein in regulating DA synaptic availability and homeostasis, which is relevant to the pathophysiology of PD. ..
  45. Singleton A, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003;302:841 pubmed
  46. Brenz Verca M, Bahi A, Boyer F, Wagner G, Dreyer J. Distribution of alpha- and gamma-synucleins in the adult rat brain and their modification by high-dose cocaine treatment. Eur J Neurosci. 2003;18:1923-38 pubmed
    b>Synucleins have attracted much attention because of their involvement in several neurodegenerative disorders...
  47. Di Monte D. The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins?. Lancet Neurol. 2003;2:531-8 pubmed
    ..Similarities between clinical and experimental findings, such as the role of pesticide exposure as a potential environmental risk factor, highlight the importance of a multidisciplinary approach to the aetiology of PD. ..
  48. Lundvig D, Lindersson E, Jensen P. Pathogenic effects of alpha-synuclein aggregation. Brain Res Mol Brain Res. 2005;134:3-17 pubmed
  49. Nishie M, Mori F, Fujiwara H, Hasegawa M, Yoshimoto M, Iwatsubo T, et al. Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol. 2004;107:292-8 pubmed
    ..Thus, the widespread accumulation of phosphorylated alpha-synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA. ..
  50. Kohno R, Sawada H, Kawamoto Y, Uemura K, Shibasaki H, Shimohama S. BDNF is induced by wild-type alpha-synuclein but not by the two mutants, A30P or A53T, in glioma cell line. Biochem Biophys Res Commun. 2004;318:113-8 pubmed
    ..These data suggest that the pathogenic alpha-SN mutations, A30P or A53T, are linked to the loss of BDNF production in glial cells. ..
  51. Moussa C, Wersinger C, Rusnak M, Tomita Y, Sidhu A. Abnormal migration of human wild-type alpha-synuclein upon gel electrophoresis. Neurosci Lett. 2004;371:239-43 pubmed
    ..These studies raise important considerations about the type of protein gel electrophoresis system suitable to study the alterations of alpha-synuclein associated with neurodegeneration, PD and other synucleinopathies. ..
  52. Kotzbauer P, Giasson B, Kravitz A, Golbe L, Mark M, Trojanowski J, et al. Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation. Exp Neurol. 2004;187:279-88 pubmed
    ..Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases. ..
  53. Bonifati V, Oostra B, Heutink P. Unraveling the pathogenesis of Parkinson's disease--the contribution of monogenic forms. Cell Mol Life Sci. 2004;61:1729-50 pubmed
    ..Moreover, we focus on the mechanisms of disease caused by alpha-synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease. ..