A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
Author
Imler, ElliotPyon, Jin Sang
Kindelay, Selina
Torvund, Meaghan
Zhang, Yong-Quan
Chandra, Sreeganga S
Zinsmaier, Konrad E
Affiliation
Univ Arizona, Grad Interdisciplinary Program NeurosciUniv Arizona, Dept Neurosci
Univ Arizona, Dept Mol & Cellular Biol, Undergrad Program Neurosci & Cognit Sci
Univ Arizona, Dept Mol & Cellular Biol
Issue Date
2019-10-30
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ELIFE SCIENCES PUBLICATIONS LTDCitation
Imler, E., Jin Sang Pyon, Kindelay, S., Torvund, M., Yong-quan Zhang, Chandra, S. S., & Zinsmaier, K. E. (2019, October 30). A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism. Retrieved January 27, 2020, from eLife website: https://elifesciences.org/articles/46607 Journal
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Copyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.Note
Open access journalISSN
2050-084XPubMed ID
31663851Version
Final published versionSponsors
National Institute of Neurological Disorders and StrokeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS083849, R21NS094809]ae974a485f413a2113503eed53cd6c53
10.7554/eLife.46607
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Except where otherwise noted, this item's license is described as Copyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License.
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