Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis

Jennifer Greaves, Kimon Lemonidis, Oforiwa Gorleku, Carlos Cruchaga, Christopher Grefen, Luke Chamberlain

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Recently, mutations in the DNAJC5 gene encoding cysteine-string protein alpha (CSPα) were identified to cause the neurodegenerative disorder adult-onset neuronal ceroid lipofuscinosis. The disease-causing mutations (L115R or ΔL116) occur within the cysteine-string domain, a region of the protein that is post-translationally modified by extensive palmitoylation. Here we demonstrate that L115R and ΔL116 mutant proteins are mis-targeted in neuroendocrine cells and form SDS-resistant aggregates, concordant with the properties of other mutant proteins linked to neurodegenerative disorders. The mutant aggregates are membrane-associated and incorporate palmitate. Indeed, co-expression of palmitoyl transferase enzymes promoted the aggregation of the CSPα mutants, and chemical depalmitoylation solubilized the aggregates, demonstrating that aggregation is induced and maintained by palmitoylation. In agreement with these observations, SDS-resistant CSPα aggregates were present in brain samples from patients carrying the L115R mutation, and were depleted by chemical depalmitoylation. In summary, this study identifies a novel interplay between genetic mutations and palmitoylation in driving aggregation of CSPα mutant proteins. We propose that this palmitoylation-induced aggregation of mutant CSPα proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis in affected families.
LanguageEnglish
Pages37330-37339
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number44
Early online date19 Aug 2012
DOIs
Publication statusPublished - 26 Oct 2012

Fingerprint

Ceroid
Lipoylation
Neuronal Ceroid-Lipofuscinoses
Mutant Proteins
Agglomeration
Mutation
Neurodegenerative Diseases
Neuroendocrine Cells
Gene encoding
Palmitates
Transferases
Cysteine
Brain
Membranes
cysteine string protein
Enzymes
Genes
Proteins

Keywords

  • exocytosis
  • protein palmitoylation
  • protein aggregation
  • protein acylation
  • membrane trafficking
  • palmitoylation-induced aggregation
  • cysteine-string protein mutants
  • neuronal ceroid lipofuscinosis

Cite this

Greaves, Jennifer ; Lemonidis, Kimon ; Gorleku, Oforiwa ; Cruchaga, Carlos ; Grefen, Christopher ; Chamberlain, Luke. / Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 44. pp. 37330-37339.
@article{26803ea227324eda87fe60c14af699d4,
title = "Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis",
abstract = "Recently, mutations in the DNAJC5 gene encoding cysteine-string protein alpha (CSPα) were identified to cause the neurodegenerative disorder adult-onset neuronal ceroid lipofuscinosis. The disease-causing mutations (L115R or ΔL116) occur within the cysteine-string domain, a region of the protein that is post-translationally modified by extensive palmitoylation. Here we demonstrate that L115R and ΔL116 mutant proteins are mis-targeted in neuroendocrine cells and form SDS-resistant aggregates, concordant with the properties of other mutant proteins linked to neurodegenerative disorders. The mutant aggregates are membrane-associated and incorporate palmitate. Indeed, co-expression of palmitoyl transferase enzymes promoted the aggregation of the CSPα mutants, and chemical depalmitoylation solubilized the aggregates, demonstrating that aggregation is induced and maintained by palmitoylation. In agreement with these observations, SDS-resistant CSPα aggregates were present in brain samples from patients carrying the L115R mutation, and were depleted by chemical depalmitoylation. In summary, this study identifies a novel interplay between genetic mutations and palmitoylation in driving aggregation of CSPα mutant proteins. We propose that this palmitoylation-induced aggregation of mutant CSPα proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis in affected families.",
keywords = "exocytosis , protein palmitoylation, protein aggregation , protein acylation , membrane trafficking , palmitoylation-induced aggregation , cysteine-string protein mutants , neuronal ceroid lipofuscinosis",
author = "Jennifer Greaves and Kimon Lemonidis and Oforiwa Gorleku and Carlos Cruchaga and Christopher Grefen and Luke Chamberlain",
year = "2012",
month = "10",
day = "26",
doi = "10.1074/jbc.M112.389098",
language = "English",
volume = "287",
pages = "37330--37339",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
number = "44",

}

Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis. / Greaves, Jennifer; Lemonidis, Kimon; Gorleku, Oforiwa; Cruchaga, Carlos; Grefen, Christopher; Chamberlain, Luke.

In: Journal of Biological Chemistry, Vol. 287, No. 44, 26.10.2012, p. 37330-37339.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis

AU - Greaves, Jennifer

AU - Lemonidis, Kimon

AU - Gorleku, Oforiwa

AU - Cruchaga, Carlos

AU - Grefen, Christopher

AU - Chamberlain, Luke

PY - 2012/10/26

Y1 - 2012/10/26

N2 - Recently, mutations in the DNAJC5 gene encoding cysteine-string protein alpha (CSPα) were identified to cause the neurodegenerative disorder adult-onset neuronal ceroid lipofuscinosis. The disease-causing mutations (L115R or ΔL116) occur within the cysteine-string domain, a region of the protein that is post-translationally modified by extensive palmitoylation. Here we demonstrate that L115R and ΔL116 mutant proteins are mis-targeted in neuroendocrine cells and form SDS-resistant aggregates, concordant with the properties of other mutant proteins linked to neurodegenerative disorders. The mutant aggregates are membrane-associated and incorporate palmitate. Indeed, co-expression of palmitoyl transferase enzymes promoted the aggregation of the CSPα mutants, and chemical depalmitoylation solubilized the aggregates, demonstrating that aggregation is induced and maintained by palmitoylation. In agreement with these observations, SDS-resistant CSPα aggregates were present in brain samples from patients carrying the L115R mutation, and were depleted by chemical depalmitoylation. In summary, this study identifies a novel interplay between genetic mutations and palmitoylation in driving aggregation of CSPα mutant proteins. We propose that this palmitoylation-induced aggregation of mutant CSPα proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis in affected families.

AB - Recently, mutations in the DNAJC5 gene encoding cysteine-string protein alpha (CSPα) were identified to cause the neurodegenerative disorder adult-onset neuronal ceroid lipofuscinosis. The disease-causing mutations (L115R or ΔL116) occur within the cysteine-string domain, a region of the protein that is post-translationally modified by extensive palmitoylation. Here we demonstrate that L115R and ΔL116 mutant proteins are mis-targeted in neuroendocrine cells and form SDS-resistant aggregates, concordant with the properties of other mutant proteins linked to neurodegenerative disorders. The mutant aggregates are membrane-associated and incorporate palmitate. Indeed, co-expression of palmitoyl transferase enzymes promoted the aggregation of the CSPα mutants, and chemical depalmitoylation solubilized the aggregates, demonstrating that aggregation is induced and maintained by palmitoylation. In agreement with these observations, SDS-resistant CSPα aggregates were present in brain samples from patients carrying the L115R mutation, and were depleted by chemical depalmitoylation. In summary, this study identifies a novel interplay between genetic mutations and palmitoylation in driving aggregation of CSPα mutant proteins. We propose that this palmitoylation-induced aggregation of mutant CSPα proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis in affected families.

KW - exocytosis

KW - protein palmitoylation

KW - protein aggregation

KW - protein acylation

KW - membrane trafficking

KW - palmitoylation-induced aggregation

KW - cysteine-string protein mutants

KW - neuronal ceroid lipofuscinosis

U2 - 10.1074/jbc.M112.389098

DO - 10.1074/jbc.M112.389098

M3 - Article

VL - 287

SP - 37330

EP - 37339

JO - Journal of Biological Chemistry

T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 44

ER -