title: Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation.
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.
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA.|Department of Neurology, Yale University, New Haven, CT, USA.|Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Henderson
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA.|Department of Neurology, Yale University, New Haven, CT, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Wirak
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA.|Department of Neurology, Yale University, New Haven, CT, USA.
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Yale Center for Analytical Services, New Haven, CT, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.affiliation: Nathan Kline Institute, Orangeburg, NY, USA.|Departments of Psychiatry and Physiology and Neuroscience, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Dolzhanskaya
authors.affiliation: Department of Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.|Biogen Idec, Cambridge, MA, 02142, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.affiliation: Department of Neurology, St. Elisabeth Hospital, 5022 GC, Tilburg, Netherlands.
authors.forename: Peter C G
authors.initials: PC
authors.lastname: Nijssen
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
authors.forename: TuKiet T
authors.initials: TT
authors.lastname: Lam
authors.affiliation: Department of Pharmacology, Wayne State University, Detroit, MI, USA.
authors.forename: Amy F
authors.initials: AF
authors.lastname: Roth
authors.affiliation: Department of Pharmacology, Wayne State University, Detroit, MI, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Glyn
authors.initials: G
authors.lastname: Dawson
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, New York, NY, USA.|Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.|Department of Neurology, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.|Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.|Department of Molecular Cell and Developmental Biology, Yale University, New Haven, CT, USA. sreeganga.chandra@yale.edu.
authors.forename: Sreeganga S
authors.initials: SS
authors.lastname: Chandra
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D054878:Lipoylation / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D060066:Protein Interaction Maps; D040901:Proteomics; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D013869:Thiolester Hydrolases / Q000378:metabolism*; D014162:Transfection
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase
keywords: Cysteine-string protein alpha (CSPα); Neurodegeneration; Neuronal ceroid lipofuscinosis (NCL); Palmitoyl-protein thioesterase 1 (PPT1); Palmitoylation