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PMID: 10407019 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 19 ·No. 14 ·1999-07-15 ·Pages 5782-91

Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B

Abstract

alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of alpha-synuclein inhibits protein kinase C activity. The association of alpha-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases.

MeSH Terms
14-3-3 Proteins Amino Acid Sequence Amino Acid Substitution Binding Sites Cell Line Cloning, Molecular Enzyme Inhibitors/chemistry,metabolism Gene Expression Regulation Humans Molecular Sequence Data Nerve Tissue Proteins/chemistry,genetics,metabolism Phosphoproteins/chemistry,metabolism Point Mutation Protein Kinase C/antagonists & inhibitors,metabolism Proteins/chemistry,genetics,metabolism Recombinant Proteins/chemistry,metabolism Sequence Alignment Sequence Homology, Amino Acid Synucleins Transfection Tyrosine 3-Monooxygenase alpha-Synuclein
Chemicals
14-3-3 Proteins Enzyme Inhibitors Nerve Tissue Proteins Phosphoproteins Proteins Recombinant Proteins SNCA protein, human Synucleins alpha-Synuclein Tyrosine 3-Monooxygenase Protein Kinase C
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ostrerova N
Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Petrucelli L
Farrer M
Mehta N
Choi P
Hardy J
Wolozin B
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
1999-07-15
Pages
5782-91
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6783081
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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