title: Contrasting effects of α-synuclein and γ-synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses.
abstract: In neuronal synapses, neurotransmitter-loaded vesicles fuse with presynaptic plasma membrane in a complex sequence of tightly regulated events. The assembly of specialized SNARE complexes plays a pivotal role in this process. The function of the chaperone cysteine string protein α (CSPα) is important for synaptic SNARE complex formation, and mice lacking this protein develop severe synaptic dysfunction and neurodegeneration that lead to their death within 3 months after birth. Another presynaptic protein, α-synuclein, also potentiates SNARE complex formation, and its overexpression rescues the phenotype of CSPα null mutant mice, although these two proteins use different mechanisms to achieve this effect. α-Synuclein is a member of a family of three related proteins whose structural similarity suggests functional redundancy. Here, we assessed whether γ-synuclein shares the ability of α-synuclein to bind synaptic vesicles and ameliorate neurodegeneration caused by CSPα deficiency in vivo. Although the N-terminal lipid-binding domains of the two synucleins showed similar affinity for purified synaptic vesicles, the C-terminal domain of γ-synuclein was not able to interact with synaptobrevin-2/VAMP2. Consequently, overexpression of γ-synuclein did not have any noticeable effect on the phenotype of CSPα null mutant mice. Our data suggest that the functions of α- and γ-synucleins in presynaptic terminals are not fully redundant.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ninkina
authors.forename: Owen M
authors.initials: OM
authors.lastname: Peters
authors.forename: Natalie
authors.initials: N
authors.lastname: Connor-Robson
authors.forename: Olga
authors.initials: O
authors.lastname: Lytkina
authors.forename: Essam
authors.initials: E
authors.lastname: Sharfeddin
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051845:gamma-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein; C088460:cysteine string protein; D051845:gamma-Synuclein