TY - JOUR
T1 - A drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
AU - Imler, Elliot
AU - Pyon, Jin Sang
AU - Kindelay, Selina
AU - Torvund, Meaghan
AU - Zhang, Yong Quan
AU - Chandra, Sreeganga S.
AU - Zinsmaier, Konrad E.
N1 - Funding Information: We thank Drs. Hugo J. Bellen (Baylor College of Medicine, Houston TX, USA), P. Robin Heisinger (Freie Universität, Berlin, Germany), Patrik Verstreken (VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium), and the Developmental Studies Hybridoma Bank at the University of Iowa for antibodies and/or fly strains. We thank Patty Jansma, Andrea Wellington, Stephan Dong, Marija Zaruba, Mays Imad, David Tyler Eves, Jamie Ramirez, Eleazar Togawa Moreno, and Milos Babic for their technical help and critical feedback. This work was supported by grants from NINDS (R01 NS083849 to SSC (PI) and KEZ (subaward); R21 NS094809 to KEZ). Funding Information: We thank Drs. Hugo J. Bellen (Baylor College of Medicine, Houston TX, USA), P. Robin Heisinger (Freie Universit?t, Berlin, Germany), Patrik Verstreken (VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium), and the Developmental Studies Hybridoma Bank at the University of Iowa for antibodies and/or fly strains. We thank Patty Jansma, Andrea Wellington, Stephan Dong, Marija Zaruba, Mays Imad, David Tyler Eves, Jamie Ramirez, Eleazar Togawa Moreno, and Milos Babic for their technical help and critical feedback. This work was supported by grants from NINDS (R01 NS083849 to SSC (PI) and KEZ (subaward); R21 NS094809 to KEZ). Publisher Copyright: © 2019, eLife Sciences Publications Ltd. All rights reserved.
PY - 2019/10
Y1 - 2019/10
N2 - 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 ubiquitinateproteins 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.
AB - 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 ubiquitinateproteins 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.
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U2 - https://doi.org/10.7554/eLife.46607
DO - https://doi.org/10.7554/eLife.46607
M3 - Article
C2 - 31663851
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e46607
ER -