Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

Cysteine string protein (CSP alpha) is a presynaptic J protein co-chaperone that opposes neurodegeneration. Mutations in CSP alpha (i.e., Leu115 to Arg substitution or deletion (Delta) of Leu116) cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly inherited neurodegenerative disease. We have previously demonstrated that CSP alpha 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 BK alpha subunit is elevated similar to 2.5 fold in the post-mortem cortex of a 36-year-old patient with the Leu116. CSP alpha mutation. Moreover, we find that the increase in BK alpha subunit level is selective for ANCL and not a general feature of neurodegenerative conditions. While reduced levels of CSP alpha are found in some postmortem cortex specimens from Alzheimer's disease patients, we find no concomitant increase in BK alpha subunit expression in Alzheimer's specimens. Both CSP alpha monomer and oligomer expression are reduced in synaptosomes prepared from ANCL cortex compared with control. In a cultured neuronal cell model, CSP alpha oligomers are short lived. The results of this study indicate that the Leu116 Delta mutation leads to elevated BK alpha subunit levels in human cortex and extend our initial work in rodent models demonstrating the modulation of BK alpha subunit levels by the same CSP alpha 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.