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

Ninkina, Natalia ORCID: https://orcid.org/0000-0001-8570-5648, Peters, Owen Morgan ORCID: https://orcid.org/0000-0002-6824-0663, Connor-Robson, Natalie ORCID: https://orcid.org/0000-0001-8350-6928, Lytkina, Olga, Sharfeddin, Essam and Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352 2012. 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. Journal of Biological Chemistry 287 (53) , pp. 44471-44477. 10.1074/jbc.M112.422402

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QR Microbiology
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Last Modified:	12 Dec 2022 08:36
URI:	https://orca.cardiff.ac.uk/id/eprint/57134

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