TY - JOUR
T1 - α-Synuclein shares physical and functional homology with 14-3-3 proteins
AU - Ostrerova, Natalie
AU - Petrucelli, Leonard
AU - Farrer, Matthew
AU - Mehta, Nitinkumar
AU - Choi, Peter
AU - Hardy, John
AU - Wolozin, Benjamin
PY - 1999/7/15
Y1 - 1999/7/15
N2 - α-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in α-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of α-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that α-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of α- synuclein and 14-3-3 proteins share over 40% homology. In addition, α- 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 α- synuclein inhibits protein kinase C activity. The association of α-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of α-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type α-synuclein is toxic, and overexpression of α-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of α-synuclein suggests that it might act as a protein chaperone and that accumulation of α-synuclein could contribute to cell death in neurodegenerative diseases.
AB - α-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in α-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of α-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that α-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of α- synuclein and 14-3-3 proteins share over 40% homology. In addition, α- 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 α- synuclein inhibits protein kinase C activity. The association of α-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of α-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type α-synuclein is toxic, and overexpression of α-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of α-synuclein suggests that it might act as a protein chaperone and that accumulation of α-synuclein could contribute to cell death in neurodegenerative diseases.
KW - 14-3-3 proteins
KW - Alzheimer's disease
KW - Apoptosis
KW - BAD
KW - Extracellular regulated kinase
KW - Parkinson's disease
KW - Protein kinase C
KW - Synuclein
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UR - http://www.scopus.com/inward/citedby.url?scp=0033565874&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.19-14-05782.1999
DO - 10.1523/jneurosci.19-14-05782.1999
M3 - Article
C2 - 10407019
AN - SCOPUS:0033565874
SN - 0270-6474
VL - 19
SP - 5782
EP - 5791
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 14
ER -