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

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.

Palmitoylation: A New Therapeutic Target for Parkinson's Disease?

“…Ho et al 2 tackled this in a comprehensive study describing the relationship between α‐synuclein and Syt11 and the role of palmitoylation (the addition of palmitate to cysteine) of Syt11 using mouse/human brain tissue and cultured neurons (Fig. 1).…”

“…Membrane association is an important aspect of α‐synuclein physiology and alters the balance of α‐synuclein tetramers and aggregation‐prone monomers. Ho et al 2 showed that palmitoylated Syt11 (and hence lipid bilayer curvature) shifted this equilibrium, increasing the aggregation‐prone monomeric form of α‐synuclein without a direct interaction between Syt11 and α‐synuclein.…”

“…The factors that disrupt α‐synuclein equilibrium and initiate misfolding and eventual cytotoxicity are not clearly understood; aging, environmental influences, and toxins have been proposed 3 . Ho et al 2 have demonstrated how palmitoylated Syt11 can tilt the balance of α‐synuclein toward aggregation‐prone conformations. However, the role of palmitoylation is complex.…”

“…1 Whether this PD-like pathogenicity is associated with α-synuclein aggregation has not been explored, and the specific interaction between α-synuclein and Syt11 was unknown. Ho et al 2 this in a comprehensive study describing the relationship between α-synuclein and Syt11 and the role of palmitoylation (the addition of palmitate to cysteine) of Syt11 using mouse/human brain tissue and cultured neurons (Fig. 1).…”

Mechanistic Insights into S-Depalmitolyse Activity of Cln5 Protein Linked to Neurodegeneration and Batten Disease: A QM/MM Study

“…43−45 Additionally, S-depalmitoylation has a significant impact on neuronal development and synaptic plasticity and is associated with various neurological diseases such as Alzheimer's, Huntington's, and Parkinson's. 46,47 Luebben et al 22 conducted the reaction depicted in Scheme 1 to mimic the process of S-depalmitoylation by utilizing fluorescent emission spectroscopy techniques. 48 A recently synthesized fluorescent probe called DPP-5 49 was employed, comprising a long-chain palmitic group (tail) connected to a fluorescent group R (head) by a sulfur atom.…”