Abstract
Cysteine string protein α (CSPα) is a vesicle protein located in the presynaptic terminal of most synapses. CSPα is an essential molecular co-chaperone that facilitates the correct folding of proteins and the assembly of the exocytic machinery. The absence of this protein leads to altered neurotransmitter release and neurodegeneration in multiple model systems, from flies to mice. In humans, CSPα mutations are associated with the development of neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disease characterized by intracellular accumulation of lysosomal material. Here, we review the physiological role of CSPα and the pathology resulting from the homozygous deletion of the gene or its mutations. In addition, we investigate whether long-term moderate reduction of the protein produces motor dysfunction. We found that 1-year-old CSPα heterozygous mice display a reduced ability to sustain motor unit recruitment during repetitive stimulation, which indicates that physiological levels of CSPα are required for normal neuromuscular responses in mice and, likely, in humans.
Highlights
Reviewed by: Janice Eva Arlee Braun, University of Calgary, Canada Konrad Ernst Zinsmaier, University of Arizona, USA
Cysteine string protein α (CSPα) is a vesicle protein located in the presynaptic terminal of most synapses
CSPα mutations are associated with the development of neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disease characterized by intracellular accumulation of lysosomal material
Summary
Cysteine string protein α (CSPα) (Dnajc5) is a highly conserved protein (Figure 1A) typically associated with the membrane of synaptic vesicles and secretory granules (Zinsmaier et al, 1990). It contains a DNA-J domain characteristic of Hsp co-chaperones. This domain interacts with the 70 kDa heat shock cognate protein (Hsc70) (Braun et al, 1996) and regulates the refolding of client proteins (Hennessy et al, 2005). The cysteine string domain is approximately 25-amino-acids long and contains 13–15 cysteines, most of them palmitoylated. CSPα contains a C-terminal domain, the function of which is not well-understood
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