TY - JOUR
T1 - α-Synuclein cooperates with CSPα in preventing neurodegeneration
AU - Chandra, Sreeganga
AU - Gallardo, Gilbert
AU - Fernández-Chacón, Rafael
AU - Schlüter, Oliver M.
AU - Südhof, Thomas C.
N1 - Funding Information:
We thank M. Goedert (MRC, Cambridge, United Kingdom) for transgenic Thy-1 expression vector, V. Buchman (Cardiff University, United Kingdom) for γ-synuclein KO mice, R. Joho and C. Street for assistance in the force-plate actometry, R.E. Hammer and H. Riedesel for assistance in generating transgenic mice, N. Hamlin for extensive help with animal studies, I. Kornblum and A. Roth for technical assistance, and M.S. Brown and J.L. Goldstein for advice. This study was partly supported by grants from the N.I.H. (5 R01 NS40057-04 to T.C.S.), the American Parkinson Disease Association (to S.C.), and the Spanish Ministry of Science and Technology and FEDER (BFI2001-4959-E and BFI2002-01686; to R.F.-C.).
PY - 2005/11/4
Y1 - 2005/11/4
N2 - α-synuclein and cysteine-string protein-α (CSPα) are abundant synaptic vesicle proteins independently linked to neurodegeneration. Dominantly inherited mutations in α-synuclein cause Parkinson's disease, but the physiological role of α-synuclein remains unknown. Deletion of CSPα produces rapidly progressive neurodegeneration in mice, presumably because the cochaperone function of CSPα is essential for neuronal survival. Here, we report the surprising finding that transgenic expression of α-synuclein abolishes the lethality and neurodegeneration caused by deletion of CSPα. Conversely, ablation of endogenous synucleins exacerbates these phenotypes. Deletion of CSPα inhibits SNARE complex assembly; transgenic α-synuclein ameliorates this inhibition. In preventing neurodegeneration in CSPα-deficient mice, α-synuclein does not simply substitute for CSPα but acts by a downstream mechanism that requires phospholipid binding by α-synuclein. These observations reveal a powerful in vivo activity of α-synuclein in protecting nerve terminals against injury and suggest that this activity operates in conjunction with CSPα and SNARE proteins on the presynaptic membrane interface.
AB - α-synuclein and cysteine-string protein-α (CSPα) are abundant synaptic vesicle proteins independently linked to neurodegeneration. Dominantly inherited mutations in α-synuclein cause Parkinson's disease, but the physiological role of α-synuclein remains unknown. Deletion of CSPα produces rapidly progressive neurodegeneration in mice, presumably because the cochaperone function of CSPα is essential for neuronal survival. Here, we report the surprising finding that transgenic expression of α-synuclein abolishes the lethality and neurodegeneration caused by deletion of CSPα. Conversely, ablation of endogenous synucleins exacerbates these phenotypes. Deletion of CSPα inhibits SNARE complex assembly; transgenic α-synuclein ameliorates this inhibition. In preventing neurodegeneration in CSPα-deficient mice, α-synuclein does not simply substitute for CSPα but acts by a downstream mechanism that requires phospholipid binding by α-synuclein. These observations reveal a powerful in vivo activity of α-synuclein in protecting nerve terminals against injury and suggest that this activity operates in conjunction with CSPα and SNARE proteins on the presynaptic membrane interface.
UR - https://www.scopus.com/pages/publications/27544507306
U2 - 10.1016/j.cell.2005.09.028
DO - 10.1016/j.cell.2005.09.028
M3 - Article
C2 - 16269331
AN - SCOPUS:27544507306
SN - 0092-8674
VL - 123
SP - 383
EP - 396
JO - Cell
JF - Cell
IS - 3
ER -