Palmitoylation of the Parkinson’s disease–associated protein synaptotagmin-11 links its turnover to α-synuclein homeostasis

Author:

Ho Gary P. H.1ORCID,Wilkie Erin C.1,White Andrew J.1,Selkoe Dennis J.1ORCID

Affiliation:

1. Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 USA.

Abstract

Synaptotagmin-11 (Syt11) is a vesicle-trafficking protein that is linked genetically to Parkinson’s disease (PD). Likewise, the protein α-synuclein regulates vesicle trafficking, and its abnormal aggregation in neurons is the defining cytopathology of PD. Because of their functional similarities in the same disease context, we investigated whether the two proteins were connected. We found that Syt11 was palmitoylated in mouse and human brain tissue and in cultured cortical neurons and that this modification to Syt11 disrupted α-synuclein homeostasis in neurons. Palmitoylation of two cysteines adjacent to the transmembrane domain, Cys 39 and Cys 40 , localized Syt11 to digitonin-insoluble portions of intracellular membranes and protected it from degradation by the endolysosomal system. In neurons, palmitoylation of Syt11 increased its abundance and enhanced the binding of α-synuclein to intracellular membranes. As a result, the abundance of the physiologic tetrameric form of α-synuclein was decreased, and that of its aggregation-prone monomeric form was increased. These effects were replicated by overexpression of wild-type Syt11 but not a palmitoylation-deficient mutant. These findings suggest that palmitoylation-mediated increases in Syt11 amounts may promote pathological α-synuclein aggregation in PD.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

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