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

Elliot Imler,Meaghan Torvund,Yong-Quan Zhang,Selina Kindelay,Sreeganga S Chandra,Konrad E Zinsmaier,Jin Sang Pyon

doi:10.7554/elife.46607

Elliot Imler, Meaghan Torvund + Show 5 more

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https://doi.org/10.7554/elife.46607

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Journal: eLife	Publication Date: Oct 30, 2019
Citations: 14	License type: CC BY 4.0

Affiliation: University of Arizona, Yale University

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.

Highlights

neuronal ceroid lipofuscinoses (NCL) comprise a group of progressive neurodegenerative diseases with 14 known disease-associated genes, termed CLN1-14 (Haltia, 2003; Haltia and Goebel, 2013; Jalanko and Braulke, 2009; Mole and Cotman, 2015)
Expressed human CSPa (hCSPa) was efficiently trafficked to axon terminals and co-localized with endogenous dCSP in the neuropil of the larval ventral nerve cord (VNC; Figure 1B) and larval neuromuscular junctions (NMJs; Figure 1C)
Increasing wild type (WT) dCSP or hCSPa levels enhanced the oligomerization and lethality of CLN4 mutations. These results suggest that the respective phenotypes are due to a hypermorphic gain of function mutation that increases an activity of hCSPa

Summary

Introduction

NCLs comprise a group of progressive neurodegenerative diseases with 14 known disease-associated genes, termed CLN1-14 (Haltia, 2003; Haltia and Goebel, 2013; Jalanko and Braulke, 2009; Mole and Cotman, 2015). Understanding disease mechanisms of NCLs has implications as well for more prevalent diseases since mutations in a growing number of CLN genes cause other diseases like frontotemporal lobar degeneration, progressive epilepsy with mental retardation, spinocerebellar ataxia, retinitis pigmentosa, juvenile cerebellar ataxia, or Parkinson disease 9 (Bras et al, 2012; Mole and Cotman, 2015; Yu et al, 2010)

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