Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
Alpha-synuclein and cysteine-string protein-alpha (CSPalpha) are abundant synaptic vesicle proteins independently linked to neurodegeneration. Dominantly inherited mutations in alpha-synuclein cause Parkinson's disease, but the physiological role of alpha-synuclein remains unknown. Deletion of CSPalpha produces rapidly progressive neurodegeneration in mice, presumably because the cochaperone function of CSPalpha is essential for neuronal survival. Here, we report the surprising finding that transgenic expression of alpha-synuclein abolishes the lethality and neurodegeneration caused by deletion of CSPalpha. Conversely, ablation of endogenous synucleins exacerbates these phenotypes. Deletion of CSPalpha inhibits SNARE complex assembly; transgenic alpha-synuclein ameliorates this inhibition. In preventing neurodegeneration in CSPalpha-deficient mice, alpha-synuclein does not simply substitute for CSPalpha but acts by a downstream mechanism that requires phospholipid binding by alpha-synuclein. These observations reveal a powerful in vivo activity of alpha-synuclein in protecting nerve terminals against injury and suggest that this activity operates in conjunction with CSPalpha and SNARE proteins on the presynaptic membrane interface.
Chandra
Sreeganga
S
Center for Basic Neuroscience, Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Gallardo
Gilbert
G
Fernández-Chacón
Rafael
R
Schlüter
Oliver M
OM
Südhof
Thomas C
TC
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010743:Phospholipids / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013570:Synaptic Membranes / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051846:beta-Synuclein / Q000235:genetics
D050956:HSP40 Heat-Shock Proteins; D010743:Phospholipids; D050600:SNARE Proteins; D051844:alpha-Synuclein; D051846:beta-Synuclein