Palmitoylation-induced Aggregation of Cysteine-string Protein Mutants That Cause Neuronal Ceroid Lipofuscinosis

Abstract

Background: Specific mutations in the chaperone protein CSPα cause adult-onset neuronal ceroid lipofuscinosis.Results: These mutants form SDS-resistant aggregates in a palmitoylation-dependent manner in cell lines and brain samples from mutation carriers.Conclusion: Palmitoylation induces disease-causing CSPα mutants to form SDS-resistant aggregates.Significance: Formation of SDS-resistant CSPα aggregates may underlie development of adult-onset neuronal ceroid lipofuscinosis.

Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses in Drosophila larvae

“…In adult-onset NCL patients (also known as Kufs Disease), identified mutations in CSPα gene are found in the cysteinestring domain and are known to affect palmitoylation and its intracellular localization. 2,50 This leads to reductions in overall levels of CSPα and neurodegeneration, 47 and/or aggregation of the mutant CSPα monomers. 50 At a functional level, recent experiments using CSPα knockout mice have shown an intimate connection between CSPα, dynamin 1, SNAP-25 and exo/ endocytic coupling, elucidating a direct molecular connection for CSP to synaptic vesicle pool maintenance.…”

“…2,50 This leads to reductions in overall levels of CSPα and neurodegeneration, 47 and/or aggregation of the mutant CSPα monomers. 50 At a functional level, recent experiments using CSPα knockout mice have shown an intimate connection between CSPα, dynamin 1, SNAP-25 and exo/ endocytic coupling, elucidating a direct molecular connection for CSP to synaptic vesicle pool maintenance. 51,52 In Drosophila, palmitoylation of CSP and SNAP25 is clearly necessary for their proper trafficking within the cell, as shown by the consequences of mutations in the neuronal palmitoyl acyl transferase, Hip14.…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…A palmitoyltransferase inhibitor could be a possible way to regulate CSPa function as palmitoylation of CSPa increases aggregation seen in neuronal ceroid lipofuscinosis (Greaves et al, 2012).…”

A Mechanism Regulating G Protein-coupled Receptor Signaling That Requires Cycles of Protein Palmitoylation and Depalmitoylation

“…Palmitoylation has diverse functions, including anchoring hydrophilic proteins to membranes, sorting proteins into membrane lipid microdomains, and regulating intracellular protein trafficking, proteinprotein interactions, and degradation. Indeed, palmitoylation has important roles in several diseases, including cancer, Huntington disease, and neuronal ceroid lipofuscinosis (3)(4)(5)(6).…”