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

Elliot Imler, Jin Sang Pyon, Selina Kindelay, Yong-quan Zhang, Sreeganga S. Chandra, Konrad E. Zinsmaier
doi: https://doi.org/10.1101/579771
Elliot Imler
1Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, AZ 85721, USA;
5Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
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Jin Sang Pyon
2Undergraduate Program in Neuroscience and Cognitive Science Department of Molecular, University of Arizona, Tucson, AZ 85721, USA;
5Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
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Selina Kindelay
2Undergraduate Program in Neuroscience and Cognitive Science Department of Molecular, University of Arizona, Tucson, AZ 85721, USA;
5Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
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Yong-quan Zhang
3Departments of Neuroscience and Neurology, Yale University, New Haven, CT 06536, USA;
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Sreeganga S. Chandra
3Departments of Neuroscience and Neurology, Yale University, New Haven, CT 06536, USA;
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Konrad E. Zinsmaier
4Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA;
5Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
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Abstract

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα, which is a critical co-chaperone of Hsc70 protecting synapses from activity-dependent degeneration. We developed the first animal models of CLN4 by expressing either CLN4 mutant human CSPα (hCSPα) or Drosophila CSP (dCSP) in fly neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of mutant hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα abnormally accumulated in axons and somata, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructurally, abnormal multi-laminar membrane structures were frequently observed in axons and somata next to degenerative abnormalities. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing wild type (WT) dCSP levels and enhanced by increasing WT dCSP or hCSPα levels, which indicates that both CLN4 alleles resemble dominant hypermorphic gain of function mutations. 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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 15, 2019.
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A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
Elliot Imler, Jin Sang Pyon, Selina Kindelay, Yong-quan Zhang, Sreeganga S. Chandra, Konrad E. Zinsmaier
bioRxiv 579771; doi: https://doi.org/10.1101/579771
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A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
Elliot Imler, Jin Sang Pyon, Selina Kindelay, Yong-quan Zhang, Sreeganga S. Chandra, Konrad E. Zinsmaier
bioRxiv 579771; doi: https://doi.org/10.1101/579771

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