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Elife. 2019 Oct 30;8. pii: e46607. doi: 10.7554/eLife.46607.

A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism.

Author information

1
Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, United States.
2
Department of Neuroscience, University of Arizona, Tucson, United States.
3
Undergraduate Program in Neuroscience and Cognitive Science, Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States.
4
Department of Neuroscience, Yale University, New Haven, United States.
5
Department of Neurology, Yale University, New Haven, United States.
6
Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States.

Abstract

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

KEYWORDS:

D. melanogaster; cysteine-string protein; lysosome; neuronal ceroid lipofuscinosis; neuroscience

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