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Acta Neuropathol. 2016 Apr;131(4):621-37. doi: 10.1007/s00401-015-1512-2. Epub 2015 Dec 10.

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation.

Author information

1
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA.
2
Department of Neurology, Yale University, New Haven, CT, USA.
3
Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.
4
Yale Center for Analytical Services, New Haven, CT, USA.
5
Nathan Kline Institute, Orangeburg, NY, USA.
6
Departments of Psychiatry and Physiology and Neuroscience, New York University Langone Medical Center, New York, NY, USA.
7
Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
8
Department of Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
9
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
10
Biogen Idec, Cambridge, MA, 02142, USA.
11
Department of Neurology, St. Elisabeth Hospital, 5022 GC, Tilburg, Netherlands.
12
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
13
Department of Pharmacology, Wayne State University, Detroit, MI, USA.
14
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
15
Department of Pediatrics, Albert Einstein College of Medicine, New York, NY, USA.
16
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.
17
Department of Neurology, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.
18
Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.
19
Department of Molecular Cell and Developmental Biology, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.

Abstract

Neuronal ceroid lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSPα were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSPα is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.

KEYWORDS:

Cysteine-string protein alpha (CSPα); Neurodegeneration; Neuronal ceroid lipofuscinosis (NCL); Palmitoyl-protein thioesterase 1 (PPT1); Palmitoylation

PMID:
26659577
PMCID:
PMC4791186
DOI:
10.1007/s00401-015-1512-2
[Indexed for MEDLINE]
Free PMC Article

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