Date Published: January 20, 2017
Publisher: Public Library of Science
Author(s): Jan J. Vonk, Wondwossen M. Yeshaw, Francesco Pinto, Anita I. E. Faber, Liza L. Lahaye, Bart Kanon, Marianne van der Zwaag, Antonio Velayos-Baeza, Raimundo Freire, Sven C. van IJzendoorn, Nicola A. Grzeschik, Ody C. M. Sibon, Fanis Missirlis.
Chorea-Acanthocytosis is a rare, neurodegenerative disorder characterized by progressive loss of locomotor and cognitive function. It is caused by loss of function mutations in the Vacuolar Protein Sorting 13A (VPS13A) gene, which is conserved from yeast to human. The consequences of VPS13A dysfunction in the nervous system are still largely unspecified. In order to study the consequences of VPS13A protein dysfunction in the ageing central nervous system we characterized a Drosophila melanogaster Vps13 mutant line. The Drosophila Vps13 gene encoded a protein of similar size as human VPS13A. Our data suggest that Vps13 is a peripheral membrane protein located to endosomal membranes and enriched in the fly head. Vps13 mutant flies showed a shortened life span and age associated neurodegeneration. Vps13 mutant flies were sensitive to proteotoxic stress and accumulated ubiquitylated proteins. Levels of Ref(2)P, the Drosophila orthologue of p62, were increased and protein aggregates accumulated in the central nervous system. Overexpression of the human Vps13A protein in the mutant flies partly rescued apparent phenotypes. This suggests a functional conservation of human VPS13A and Drosophila Vps13. Our results demonstrate that Vps13 is essential to maintain protein homeostasis in the larval and adult Drosophila brain. Drosophila Vps13 mutants are suitable to investigate the function of Vps13 in the brain, to identify genetic enhancers and suppressors and to screen for potential therapeutic targets for Chorea-Acanthocytosis.
Chorea-Acanthocytosis (ChAc, MIM 200150) is a rare neurodegenerative disorder characterized by chorea, orofacial dyskinesia and psychiatric symptoms including tics (reviewed in [1,2]). In addition to the neurological symptoms, spiky red blood cells (acanthocytes) are often observed. ChAc is a recessively inherited disease caused by mutations in the VPS13A gene, hereafter called HsVPS13A [3,4]. These mutations mostly lead to absence or reduced levels of the HsVPS13A (or also called chorein) protein . Symptoms manifest on average at the age of 32 . The pathophysiology of ChAc is largely unknown and it is not clear why HsVPS13A loss of function leads to the symptoms presenting in ChAc patients. HsVPS13A is evolutionarily conserved and orthologues are present in various organisms such as Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Tetrahymena thermophila, Dyctiostelium discoidenum and Saccharomyces cerevisiae [6–8].
ChAc is a recessively inherited neurodegenerative disorder caused by loss of function mutations in the HsVPS13A gene [3,4]. The study of HsVPS13A function and the pathological mechanisms playing a role in ChAc is hampered by the limited availability of multicellular models for ChAc. Although Vps13A knock-out ChAc mouse models were generated, they possess variable or no abnormalities in brain tissue depending on the genetic background . This underscores the complexity of studying VPS13A in the central nervous system and suggests the presence of genetic factors playing a role in the phenotype induced by impaired function of VPS13A in the brain. The goal of this study was to use Drosophila melanogaster to establish a relatively simple multicellular model for ChAc and study the consequences of Vps13 dysfunction in the ageing central nervous system.