title: Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis.
abstract: Cysteine string protein (CSPα) is a presynaptic J protein co-chaperone that opposes neurodegeneration. Mutations in CSPα (i.e., Leu115 to Arg substitution or deletion (Δ) of Leu116) cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly inherited neurodegenerative disease. We have previously demonstrated that CSPα limits the expression of large conductance, calcium-activated K+ (BK) channels in neurons, which may impact synaptic excitability and neurotransmission. Here we show by western blot analysis that expression of the pore-forming BKα subunit is elevated ~2.5 fold in the post-mortem cortex of a 36-year-old patient with the Leu116∆ CSPα mutation. Moreover, we find that the increase in BKα subunit level is selective for ANCL and not a general feature of neurodegenerative conditions. While reduced levels of CSPα are found in some postmortem cortex specimens from Alzheimer's disease patients, we find no concomitant increase in BKα subunit expression in Alzheimer's specimens. Both CSPα monomer and oligomer expression are reduced in synaptosomes prepared from ANCL cortex compared with control. In a cultured neuronal cell model, CSPα oligomers are short lived. The results of this study indicate that the Leu116∆ mutation leads to elevated BKα subunit levels in human cortex and extend our initial work in rodent models demonstrating the modulation of BKα subunit levels by the same CSPα mutation. While the precise sequence of pathogenic events still remains to be elucidated, our findings suggest that dysregulation of BK channels may contribute to neurodegeneration in ANCL.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Donnelier
authors.affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Braun
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Dolzhanskaya
authors.affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Ahrendt
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Braun
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, United States of America; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
authors.affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Janice E A
authors.initials: JE
authors.lastname: Braun
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001344:Autopsy; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D050956:HSP40 Heat-Shock Proteins; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008565:Membrane Proteins; C088460:cysteine string protein