A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
Pyon, Jin Sang
Chandra, Sreeganga S
Zinsmaier, Konrad E
AffiliationUniv Arizona, Grad Interdisciplinary Program Neurosci
Univ Arizona, Dept Neurosci
Univ Arizona, Dept Mol & Cellular Biol, Undergrad Program Neurosci & Cognit Sci
Univ Arizona, Dept Mol & Cellular Biol
MetadataShow full item record
PublisherELIFE SCIENCES PUBLICATIONS LTD
CitationImler, 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
RightsCopyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Collection InformationThis 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 firstname.lastname@example.org.
AbstractThe 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.
NoteOpen access journal
VersionFinal published version
SponsorsNational 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]
- Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation.
- Authors: Henderson MX, Wirak GS, Zhang YQ, Dai F, Ginsberg SD, Dolzhanskaya N, Staropoli JF, Nijssen PC, Lam TT, Roth AF, Davis NG, Dawson G, Velinov M, Chandra SS
- Issue date: 2016 Apr
- Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis.
- Authors: Benitez BA, Sands MS
- Issue date: 2017 Jul 24
- Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.
- Authors: Nosková L, Stránecký V, Hartmannová H, Přistoupilová A, Barešová V, Ivánek R, Hůlková H, Jahnová H, van der Zee J, Staropoli JF, Sims KB, Tyynelä J, Van Broeckhoven C, Nijssen PC, Mole SE, Elleder M, Kmoch S
- Issue date: 2011 Aug 12
- Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss.
- Authors: Benitez BA, Cairns NJ, Schmidt RE, Morris JC, Norton JB, Cruchaga C, Sands MS
- Issue date: 2015 Nov 26
- Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators.
- Authors: Naseri NN, Ergel B, Kharel P, Na Y, Huang Q, Huang R, Dolzhanskaya N, Burré J, Velinov MT, Sharma M
- Issue date: 2020 Feb