title: Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss.
abstract: Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPα or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPα and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. bbenitez@dom.wustl.edu.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Norton
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D016708:Synaptophysin; C088460:cysteine string protein