Genomes and Genes
Gene Symbol: alpha synuclein
Description: synuclein alpha
Alias: NACP, PARK1, PARK4, PD1, alpha-synuclein, I+/--synuclein, non A-beta component of AD amyloid, synuclein alpha-140, synuclein, alpha (non A4 component of amyloid precursor)
Products: alpha synuclein
- Proukakis C, Houlden H, Schapira A. Somatic alpha-synuclein mutations in Parkinson's disease: hypothesis and preliminary data. Mov Disord. 2013;28:705-12 pubmed publisher..Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. ..
- Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol. 2013;73:459-71 pubmed publisher..We have identified a novel SNCA G51D mutation that causes a form of PD with unusual clinical, neuropathological, and biochemical features. ..
- Guo J, Covell D, Daniels J, Iba M, Stieber A, Zhang B, et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013;154:103-17 pubmed publisher..We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies. ..
- Rey N, Petit G, Bousset L, Melki R, Brundin P. Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol. 2013;126:555-73 pubmed publisher..Our results support the idea that α-syn can transfer along neural pathways and thereby contribute to the progression of the α-syn-related pathology. ..
- Rockenstein E, Nuber S, Overk C, Ubhi K, Mante M, Patrick C, et al. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 2014;137:1496-513 pubmed publisher..This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction. ..
- Boassa D, Berlanga M, Yang M, Terada M, Hu J, Bushong E, et al. Mapping the subcellular distribution of α-synuclein in neurons using genetically encoded probes for correlated light and electron microscopy: implications for Parkinson's disease pathogenesis. J Neurosci. 2013;33:2605-15 pubmed publisher..Our data support the conclusion that α-synuclein is involved in processes associated with the sorting, channeling, packaging, and transport of synaptic material destined for degradation. ..
- Bousset L, Pieri L, Ruiz Arlandis G, Gath J, Jensen P, Habenstein B, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575 pubmed publisher..Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies. ..
- Dikiy I, Eliezer D. N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound α-synuclein and increases its affinity for physiological membranes. J Biol Chem. 2014;289:3652-65 pubmed publisher..Furthermore, the novel BOG-bound state of N-terminally acetylated α-synuclein may serve as a model of partly helical membrane-bound intermediates with a role in α-synuclein function and dysfunction. ..
- Ghosh D, Mondal M, Mohite G, Singh P, Ranjan P, Anoop A, et al. The Parkinson's disease-associated H50Q mutation accelerates α-Synuclein aggregation in vitro. Biochemistry. 2013;52:6925-7 pubmed publisher..Understanding the aggregation mechanism of this H50Q mutant may help to establish the aggregation and phenotypic relationship of this novel mutant in PD. ..
- Oueslati A, Schneider B, Aebischer P, Lashuel H. Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo. Proc Natl Acad Sci U S A. 2013;110:E3945-54 pubmed publisher..Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. ..
- Fares M, Ait Bouziad N, Dikiy I, Mbefo M, Jovicic A, Kiely A, et al. The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet. 2014;23:4491-509 pubmed publisher..These findings suggest that the PD-linked mutations may cause neurodegeneration via different mechanisms, some of which may be independent of α-Syn aggregation. ..
- Sarafian T, Ryan C, Souda P, Masliah E, Kar U, Vinters H, et al. Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human α-synuclein. PLoS ONE. 2013;8:e63557 pubmed publisher..Overall the study showed that accumulation of full-length, N-terminally acetylated human α-synuclein was sufficient to disrupt brain mitochondrial function in adult mice. ..
- George S, Rey N, Reichenbach N, Steiner J, Brundin P. α-Synuclein: the long distance runner. Brain Pathol. 2013;23:350-7 pubmed publisher..We describe recent studies investigating cell-to-cell transfer of α-synuclein and focus our review on the long-distance axonal transport of α-synuclein along neurons. ..
- Kim C, Ho D, Suk J, You S, Michael S, Kang J, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4:1562 pubmed publisher....
- Lemkau L, Comellas G, Lee S, Rikardsen L, Woods W, George J, et al. Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K. PLoS ONE. 2013;8:e49750 pubmed publisher....
- Masuda Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128-38 pubmed publisher..This is a new mouse model of sporadic α-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy. ..
- Schildknecht S, Gerding H, Karreman C, Drescher M, Lashuel H, Outeiro T, et al. Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. J Neurochem. 2013;125:491-511 pubmed publisher..Moreover, we hypothesize that ASYN may act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging. ..
- Paslawski W, Andreasen M, Nielsen S, Lorenzen N, Thomsen K, Kaspersen J, et al. High stability and cooperative unfolding of α-synuclein oligomers. Biochemistry. 2014;53:6252-63 pubmed publisher..The high stability of the αSN oligomer indicates that therapeutic strategies should aim to prevent the formation of or passivate rather than dissociate this cytotoxic species. ..
- Ulusoy A, Rusconi R, Pérez Revuelta B, Musgrove R, Helwig M, Winzen Reichert B, et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med. 2013;5:1119-27 pubmed publisher..Thus, overexpression of human α-synuclein in the lower brainstem is sufficient to induce its long-distance caudo-rostral propagation, recapitulating features of Parkinson's disease and mechanisms of disease progression. ..
- Foulds P, Diggle P, Mitchell J, Parker A, Hasegawa M, Masuda Suzukake M, et al. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson's disease. Sci Rep. 2013;3:2540 pubmed publisher..012). Overall, we conclude that the plasma level of phosphorylated α-synuclein has potential value as a diagnostic tool, whereas the level of total α-synuclein could act as a surrogate marker for the progression of PD. ..
- Leftin A, Job C, Beyer K, Brown M. Solid-state ¹³C NMR reveals annealing of raft-like membranes containing cholesterol by the intrinsically disordered protein α-Synuclein. J Mol Biol. 2013;425:2973-87 pubmed publisher..We propose this process is implicated in regulation of synaptic membrane fusion that may be altered by aggregation of αS in Parkinson's disease. ..
- Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, et al. α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem. 2013;288:21742-54 pubmed publisher..In summary, different α-Syn species act divergently on the axonal transport machinery. These findings provide new insights into α-Syn oligomer-driven neuritic pathology as one of the earliest events in synucleinopathies. ..
- Rutherford N, Moore B, Golde T, Giasson B. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J Neurochem. 2014;131:859-67 pubmed publisher..G51D is the first SNCA mutation to show decreased α-synuclein aggregation, suggesting a distinct disease mechanism to other SNCA mutations. ..
- Ghosh D, Sahay S, Ranjan P, Salot S, Mohite G, Singh P, et al. The newly discovered Parkinson's disease associated Finnish mutation (A53E) attenuates α-synuclein aggregation and membrane binding. Biochemistry. 2014;53:6419-21 pubmed publisher..Further, A53E showed reduced membrane binding affinity compared to A53T and WT. The present study would help to delineate the role of A53E mutation in early onset PD pathogenesis. ..
- Guardia Laguarta C, Area Gomez E, Rüb C, Liu Y, Magrane J, Becker D, et al. α-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci. 2014;34:249-59 pubmed publisher..We believe that our results have far-reaching implications for both our understanding of α-syn biology and the treatment of synucleinopathies. ..
- Basso E, Antas P, Marijanovic Z, Goncalves S, Tenreiro S, Outeiro T. PLK2 modulates α-synuclein aggregation in yeast and mammalian cells. Mol Neurobiol. 2013;48:854-62 pubmed publisher..Our study supports a role for PLK2 in the generation of aSyn inclusions by a mechanism that does not depend directly on serine 129 phosphorylation. ..
- Boudes M, Uvin P, Pinto S, Voets T, Fowler C, Wenning G, et al. Bladder dysfunction in a transgenic mouse model of multiple system atrophy. Mov Disord. 2013;28:347-55 pubmed publisher..PLP-hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn-related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA...
- Irwin D, Lee V, Trojanowski J. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. 2013;14:626-36 pubmed publisher..An understanding of the relationships between these three distinct pathologies and their resultant clinical phenotypes is crucial for the development of effective disease-modifying treatments for PD and PDD. ..
- Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS ONE. 2013;8:e55375 pubmed publisher..Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD. ..
- Singh P, Kotia V, Ghosh D, Mohite G, Kumar A, Maji S. Curcumin modulates α-synuclein aggregation and toxicity. ACS Chem Neurosci. 2013;4:393-407 pubmed publisher..Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases. ..
- Mysling S, Betzer C, Jensen P, Jorgensen T. Characterizing the dynamics of α-synuclein oligomers using hydrogen/deuterium exchange monitored by mass spectrometry. Biochemistry. 2013;52:9097-103 pubmed publisher..This region has mainly been described in relation to membrane binding of αSN, and structuring may be important in relation to disease. ..
- Paumier K, Sukoff Rizzo S, Berger Z, Chen Y, Gonzales C, Kaftan E, et al. Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease. PLoS ONE. 2013;8:e70274 pubmed publisher..Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD. ..
- Goncalves S, Outeiro T. Assessing the subcellular dynamics of alpha-synuclein using photoactivation microscopy. Mol Neurobiol. 2013;47:1081-92 pubmed publisher..Finally, we found that the molecular chaperone HSP70 accelerates the entry of aSyn into the nuclear compartment. ..
- Recasens A, Dehay B, Bove J, Carballo Carbajal I, Dovero S, Perez Villalba A, et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014;75:351-62 pubmed publisher..However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans...
- Bender A, Desplats P, Spencer B, Rockenstein E, Adame A, Elstner M, et al. TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease. PLoS ONE. 2013;8:e62277 pubmed publisher..Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies. ..
- Wietek J, Haralampiev I, Amoussouvi A, Herrmann A, Stöckl M. Membrane bound α-synuclein is fully embedded in the lipid bilayer while segments with higher flexibility remain. FEBS Lett. 2013;587:2572-7 pubmed publisher..We could show that while the entire helix is well embedded in the lipid bilayer, segments with a shallower penetration and supposable higher flexibility exist. ..
- Chi Y, Armstrong G, Jones D, Eisenmesser E, Liu C. Residue histidine 50 plays a key role in protecting α-synuclein from aggregation at physiological pH. J Biol Chem. 2014;289:15474-81 pubmed publisher..Histidine carries a partial positive charge at neutral pH, and so our result suggests that positively charged His-50 plays a role in protecting αSyn from aggregation under physiological conditions. ..
- Kasten M, Klein C. The many faces of alpha-synuclein mutations. Mov Disord. 2013;28:697-701 pubmed publisher....
- Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul Mellier A, Ruggeri F, et al. The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J Biol Chem. 2014;289:21856-76 pubmed publisher..Together, our results provide novel insight into the mechanism by which this newly described PD-associated mutation may contribute to the pathogenesis of PD and related disorders...
- Hall H, Jewett M, Landeck N, Nilsson N, Schagerlöf U, Leanza G, et al. Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors. PLoS ONE. 2013;8:e64844 pubmed publisher....
- Ikeuchi T, Kakita A, Shiga A, Kasuga K, Kaneko H, Tan C, et al. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch Neurol. 2008;65:514-9 pubmed publisher..SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients. ..
- Mollenhauer B, El Agnaf O, Marcus K, Trenkwalder C, Schlossmacher M. Quantification of α-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. Biomark Med. 2010;4:683-99 pubmed publisher..We also provide specific information regarding standardized operating procedures for cerebrospinal fluid collection in PD biomarker research efforts. ..
- Ishii A, Nonaka T, Taniguchi S, Saito T, Arai T, Mann D, et al. Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies. FEBS Lett. 2007;581:4711-7 pubmed..Taken together, these findings suggest that CK2 may be involved in the hyperphosphorylation of alpha-synuclein in alpha-synucleinopathies. ..
- Lindersson E, Beedholm R, H jrup P, Moos T, Gai W, Hendil K, et al. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem. 2004;279:12924-34 pubmed publisher..The inhibitory effect of amyloid aggregates may thus be amenable to modulation by endogenous chaperones and possibly accessible for therapeutic intervention...
- 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. ..
- Lashuel H, Petre B, Wall J, Simon M, Nowak R, Walz T, et al. Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol. 2002;322:1089-102 pubmed..The formation of pore-like oligomeric structures may explain the membrane permeabilization activity of alpha-synuclein protofibrils. These structures may contribute to the pathogenesis of PD. ..
- Yanamandra K, Gruden M, Casaite V, Meskys R, Forsgren L, Morozova Roche L. α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients. PLoS ONE. 2011;6:e18513 pubmed publisher....
- Bellucci A, Navarria L, Zaltieri M, Falarti E, Bodei S, Sigala S, et al. Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson's disease. J Neurochem. 2011;116:588-605 pubmed publisher..These findings indicate that activation of the UPR pathway in the PD brain is associated with α-synuclein accumulation occurring in part within the ER. ..
- 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. ..
- Cole N, Murphy D, Lebowitz J, Di Noto L, Levine R, Nussbaum R. Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem. 2005;280:9678-90 pubmed....
- Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat. 2010;31:763-80 pubmed publisher....
- Hong L, Simon J. Binding of Cu(II) to human alpha-synucleins: comparison of wild type and the point mutations associated with the familial Parkinson's disease. J Phys Chem B. 2009;113:9551-61 pubmed publisher..g., small oligomeric species, such as dimers and trimers) relative to WT and A53T. Thus, we propose that the high affinity site is attributed to the binding of Cu(II) to those small oligomeric species. ..
- Chiba Falek O, Nussbaum R. 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. 2001;10:3101-9 pubmed..been implicated in familial Parkinson's disease (PD) while certain polymorphic alleles at a microsatellite repeat, NACP-Rep1, located approximately 10 kb upstream of the gene, have been associated with sporadic PD...
- Banerjee K, Sinha M, Pham C, Jana S, Chanda D, Cappai R, et al. Alpha-synuclein induced membrane depolarization and loss of phosphorylation capacity of isolated rat brain mitochondria: implications in Parkinson's disease. FEBS Lett. 2010;584:1571-6 pubmed publisher..The results are significant in view of the fact that alpha-synucleinopathy is involved in the pathogenesis of Parkinson's disease. ..
- Yoshimoto M, Iwai A, Kang D, Otero D, Xia Y, Saitoh T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci U S A. 1995;92:9141-5 pubmedb>NACP, a 140-amino acid presynaptic protein, is the precursor of NAC [the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease (AD) amyloid], a peptide isolated from and immunologically localized to brain amyloid of patients ..
- Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Patrick C, et al. Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci. 2008;28:4250-60 pubmed publisher..Together, these results suggest that accumulation of alpha-syn might impair survival of NPCs by interfering with the Notch signaling pathway. Similar mechanisms could be at play in PD and Lewy body disease. ..
- Paleologou K, El Agnaf O. α-Synuclein aggregation and modulating factors. Subcell Biochem. 2012;65:109-64 pubmed publisher..The current and most recent findings regarding the factors modulating a-syn aggregation process are discussed in detail. ..
- Ozawa T, Healy D, Abou Sleiman P, Ahmadi K, Quinn N, Lees A, et al. The alpha-synuclein gene in multiple system atrophy. J Neurol Neurosurg Psychiatry. 2006;77:464-7 pubmed..No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases. ..
- Bussell R, Eliezer D. Effects of Parkinson's disease-linked mutations on the structure of lipid-associated alpha-synuclein. Biochemistry. 2004;43:4810-8 pubmed..The potential implications of these results for the role of alphaS in PD are discussed. ..
- Murray I, Giasson B, Quinn S, Koppaka V, Axelsen P, Ischiropoulos H, et al. Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry. 2003;42:8530-40 pubmed..Thus, the carboxy-terminus of alpha-syn may regulate aggregation of full-length alpha-syn and determine the diameter of alpha-syn filaments. ..
- Inglis K, Chereau D, Brigham E, Chiou S, Schöbel S, Frigon N, et al. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem. 2009;284:2598-602 pubmed publisher..These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system. ..
- Kisos H, Pukaß K, Ben Hur T, Richter Landsberg C, Sharon R. Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. PLoS ONE. 2012;7:e46817 pubmed publisher..Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA. ..