title: A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis.
abstract: Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSPα). The disease-causing mutations, which result in substitution of leucine-115 with an arginine (L115R) or deletion of the neighbouring leucine-116 (∆L116) in the cysteine-string domain cause CSPα to form high molecular weight SDS-resistant aggregates, which are also present in post-mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-string domain, however the regions of the mutant proteins that drive aggregation have not been determined. The importance of specific residues in the cysteine-string domain was investigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSPα mutants. Interestingly, palmitoylated monomers of ANCL CSPα mutants were shown to be short-lived compared with wild-type CSPα, suggesting that the mutants either have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSPα that promote aggregation in the presence of L115R/∆L116 mutations and reveal a change in the lifetime of palmitoylated monomers of the mutant proteins.
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK.
authors.forename: Cinta
authors.initials: C
authors.lastname: Diez-Ardanuy
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Greaves
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Munro
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
authors.forename: Nicholas C O
authors.initials: NC
authors.lastname: Tomkinson
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK. luke.chamberlain@strath.ac.uk.
authors.forename: Luke H
authors.identifier: 0000-0002-8701-4995
authors.initials: LH
authors.lastname: Chamberlain
mesh_terms: D003545:Cysteine / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D054878:Lipoylation; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology*; D066263:Protein Aggregation, Pathological; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein; D003545:Cysteine