# Cysteine-string Protein and Neurodegeneration

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2020 · $422,125

## Abstract

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.

## Key facts

- **NIH application ID:** 10039978
- **Project number:** 1R21NS117855-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** KONRAD ERNST ZINSMAIER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,125
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039978

## Citation

> US National Institutes of Health, RePORTER application 10039978, Cysteine-string Protein and Neurodegeneration (1R21NS117855-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10039978. Licensed CC0.

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