Chamberlain Lab

Slide 1

Twitter Feeds

Neuronal Ceroid Lipofuscinoses (NCLs) are a family of neurodegenerative lysosomal storage disorders, associated with a hallmark accumulation of autofluorescent material in neurons and other cells of the body; there are no known cures for these disorders. NCLs are broadly classified as infantile, juvenile and adult depending upon the age of symptomatic onset. The genetic mutations that cause different NCLs have been identified, and predominantly encode lysosomal or endoplasmic reticulum proteins; e.g., mutations in the CLN1 gene encoding protein palmitoyl thioesterase 1 (PPT1), which depalmitoylates proteins during lysosomal degradation, can cause infantile NCL.

Symptoms of adult-onset NCL (ANCL) usually precipitate before the age of 40 and include movement disorders, dementia, seizures and cognitive decline. Unlike other NCLs, which tend to be autosomal-recessive, ANCL can also be autosomal-dominant. Recent studies identified mutations in the DNAJC5 gene encoding cysteine-string protein (CSP) as the cause of autosomal-dominant ANCL in ~ 25% of cases investigated. These mutations are situated within a region of CSP that is extensively S-acylated.

We have shown that ANCL mutations cause CSP to form SDS-resistant aggregates. This is an intriguing observation as protein aggregation is a hallmark feature of many neurodegenerative disorders. Interestingly, we demonstrated that aggregation of the ANCL mutant CSP proteins is induced and maintained by S-acylation, and we are currently investigating the potential of specific zDHHC enzymes to serve as novel drug targets for the treatment of this neurodegenerative disease.

Past/Present Sponsors

MRC 

 Wellcome Trust

Diabetes UK

BBSRC

SULSA  

Palmitoylation

Palmitoylation is the most prominent type of S-acylation and involves the covalent and reversible attachment of a 16 carbon saturated fatty acid (palmitic acid) to cysteines of target proteins.