Cysteine-string Protein and Neurodegeneration

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The necessity of understanding causes of neurodegenerative diseases and developing potential treatments is increasing as life expectancy is extending. Neuronal ceroid lipofuscinoses (NCLs; also known as Batten disease) comprise a group of 14 monogenic neurodegenerative diseases with lysosomal pathology (CLN1-14). NCLs are typically due to recessive mutations in genes that mediate lysosomal function or ER-lysosomal trafficking with one atypical exception: the dominantly inherited NCL CLN4, which is caused by mutations in the synaptic vesicle (SV) protein CSPα. Normally, CSPα is critical to maintain synaptic function and prevent activity-dependent neurodegeneration. It also mediates the clearance of aggregating proteins like TDP-43 or α-synuclein by unconventional secretion pathways. Little is known about CLN4 disease etiology besides biochemical evidence that CLN4-causing mutations induce the formation of ubiquitinated CSPα oligomers/aggregates. Whether and how the oligomeric or monomeric protein causes lysosomal failure, neurodegeneration, and premature death remains enigmatic. We have established the first animal models of CLN4 by expressing disease-causing human CSPα (hCSPα) or fly CSP (dCSP) in Drosophila neurons. Both models recapitulate the biochemical pathology of CLN4 post-mortem brains. Further analysis revealed a novel link between CLN4 mutant CSP and prelysosomal failure. Unexpectedly, we also found that the dominant CLN4 alleles act as hypermorphic gain of function mutations inducing the oligomerization of CSP, prelysosomal failure, neurodegeneration, and lethality. We suggest that hypermorphic CLN4 mutations increase the affinity for some or one of CSP’s protein interaction causing disease. Next to an exaggerated dimerization of CSP leading to oligomerization, CLN4 mutations increase interactions of CSP with the synaptically localized palmitoyl-transferase Hip14 that could lead to prelysosomal failure. Finally, increased interactions of CSP with Hsc70 on endosomes destined to form multivesicular bodies may interfere with their processing, sorting and/or trafficking. We propose to test these possibilities by genetic approaches to better understand both the mechanisms underlying CSP’s normal neuroprotective role, and the mechanisms underlying the hypermorphic CLN4 mutations causing protein aggregation, lysosomal failure, neurodegeneration, and premature death. Uncovering mechanisms underlying CLN4 may inform the future development of therapeutic interventions. In addition, a better understanding of CSP’s neuroprotective role is important for various other neurodegenerative diseases that may be attenuated by CSP’s clearance of misfolded proteins.