Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease

Mezey, Éva; Dehejia, Anindya; Harta, G; Tresser, Nancy; Suchy, Sharon F.; Nussbaum, Robert L.; Brownstein, Michael J.; Polymeropoulos, M H

doi:10.1038/sj.mp.4000446

Cited by 118 publications

(79 citation statements)

References 17 publications

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“…␣-Synuclein has been implicated in the etiology of several neurodegenerative disorders, including dementia with Lewy bodies, multiple system atrophy, and Parkinson's disease (26)(27)(28). In Parkinson's disease, there is selective loss of dopaminergic neurons and the presence of Lewy bodies, which are largely composed of ␣-synuclein.…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

Liang

Spence

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

124

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Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naïve, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. ␣-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing ␣-synuclein in the iP and iNP rats. Similar to ␣-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3 UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3 UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the ␣-synuclein gene may contribute to alcohol preference in the iP rats.

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Section: Discussionmentioning

confidence: 99%

α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

Liang

Spence

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

124

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“…In vivo studies have shown that the majority of ␣-synuclein moves along axons in the slow component with the remainder travelling in the fast component of axonal transport (Jensen et al, 1998;Jensen et al, 1999). Aggregates of ␣-synuclein are present in brain in Parkinson's disease (Polymeropoulos et al, 1997;Mezey et al, 1998;Kruger et al, 1998), dementia with Lewy bodies (Spillantini et al, 1997), and 60-70% of AD cases (Mukaetova-Ladinska et al, 2000;Hamilton, 2000). Dysfunctional axonal transport has also been proposed as a mechanism involved in the pathogenesis of Parkinson's disease (Lach et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Molecular motors implicated in the axonal transport of tau and α-synuclein

Utton

Noble

Hill

et al. 2005

Journal of Cell Science

145

123

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“…Lewy pathology is also found in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, in neurodegeneration with brain iron accumulation type I and in glial cytoplasmic inclusions of multiple system atrophy. These diseases are collectively known as "␣-synucleinopathies" (2,3). ␣-Synuclein is likely to play a role in PD, since two missense mutations in ␣-synuclein (A53T and A30P) cause autosomal dominant, early-onset PD (4,5), and animal models overexpressing ␣-synuclein develop a disease phenotype with Lewy body-like pathology and locomotor impairment (6,7).…”

mentioning

confidence: 99%

α-Synuclein Is Degraded by Both Autophagy and the Proteasome

Webb

Ravikumar

Atkins

et al. 2003

Journal of Biological Chemistry

1,327

1,075

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Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. ␣-Synuclein is the major protein in Lewy bodies and rare mutations in ␣-synuclein cause early-onset PD. Consequently, ␣-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of ␣-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T ␣-synuclein can be switched on and off. We have used a panel of inhibitors/ stimulators of autophagy and proteasome function and followed ␣-synuclein degradation in these cells. We found that not only is ␣-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of ␣-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of ␣-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

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Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease

Cited by 118 publications

References 17 publications

α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

Molecular motors implicated in the axonal transport of tau and α-synuclein

α-Synuclein Is Degraded by Both Autophagy and the Proteasome

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