PT - JOURNAL ARTICLE AU - Jacqueline Burré AU - Manu Sharma AU - Thomas C. Südhof TI - Systematic Mutagenesis of α-Synuclein Reveals Distinct Sequence Requirements for Physiological and Pathological Activities AID - 10.1523/JNEUROSCI.3545-12.2012 DP - 2012 Oct 24 TA - The Journal of Neuroscience PG - 15227--15242 VI - 32 IP - 43 4099 - http://www.jneurosci.org/content/32/43/15227.short 4100 - http://www.jneurosci.org/content/32/43/15227.full SO - J. Neurosci.2012 Oct 24; 32 AB - α-Synuclein is an abundant presynaptic protein that binds to phospholipids and synaptic vesicles. Physiologically, α-synuclein functions as a SNARE-protein chaperone that promotes SNARE-complex assembly for neurotransmitter release. Pathologically, α-synuclein mutations and α-synuclein overexpression cause Parkinson's disease, and aggregates of α-synuclein are found as Lewy bodies in multiple neurodegenerative disorders (“synucleinopathies”). The relation of the physiological functions to the pathological effects of α-synuclein remains unclear. As an initial avenue of addressing this question, we here systematically examined the effect of α-synuclein mutations on its physiological and pathological activities. We generated 26 α-synuclein mutants spanning the entire molecule, and analyzed them compared with wild-type α-synuclein in seven assays that range from biochemical studies with purified α-synuclein, to analyses of α-synuclein expression in cultured neurons, to examinations of the effects of virally expressed α-synuclein introduced into the mouse substantia nigra by stereotactic injections. We found that both the N-terminal and C-terminal sequences of α-synuclein were required for its physiological function as SNARE-complex chaperone, but that these sequences were not essential for its neuropathological effects. In contrast, point mutations in the central region of α-synuclein, referred to as nonamyloid β component (residues 61–95), as well as point mutations linked to Parkinson's disease (A30P, E46K, and A53T) increased the neurotoxicity of α-synuclein but did not affect its physiological function in SNARE-complex assembly. Thus, our data show that the physiological function of α-synuclein, although protective of neurodegeneration in some contexts, is fundamentally distinct from its neuropathological effects, thereby dissociating the two activities of α-synuclein.