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.
Highlights
Cysteine string protein (CSPα) is a synaptic vesicle protein and molecular chaperone that is essential for neuroprotection
BKα subunit expression was evaluated in crude synaptosome fractions (P2) prepared from a post-mortem adult neuronal ceroid lipofuscinosis (ANCL) cortex sample obtained from a 36 year old male with the CSPα mutation
To examine if the CSPα-related changes in synaptic protein machinery are involved in diseases other than ANCL, we investigated the expression of BKα subunit levels in post-mortem Alzheimer’s disease (AD) cortex samples
Summary
Cysteine string protein (CSPα) is a synaptic vesicle protein and molecular chaperone that is essential for neuroprotection. The mutations L115R and L116Δ that cause ANCL are in the cysteine string region and disrupt anchoring of CSPα to synaptic vesicles [5], most likely leading to a loss-of-chaperone-function at the synaptic vesicle and a toxic gain-of-function of mis-localized CSPα. The assembly of CSPα with Hsc (heat shock cognate protein of 70kDa) and SGT (small glutamine rich tetratricopeptide repeat protein) to prevent synapse loss is an important feature of current models of the biochemical pathway underlying CSPα-mediated-neuroprotection [6,10,11,12]. In general, are responsible for the dynamic balance between promoting protein folding and directing proteins to degradation via the quality control machineries, the conformational work performed by the CSPα/Hsc70/SGT complex is likely important for maintaining the functional integrity of presynaptic protein clients
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