Yeast model based study identified myosin and calcium-dependent calmodulin signalling as a potential target for drug intervention in chorea-acanthocytosis

Author:

Soczewka Piotr1,Kolakowski Damian1,Rooij Iwona Smaczynska-de2,Rzepnikowska Weronika1,Ayscough Kathryn R.2,Kaminska Joanna1,Zoladek Teresa1ORCID

Affiliation:

1. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02106 Warsaw, Poland

2. Department of Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK

Abstract

Chorea-acanthocytosis (ChAc) is a rare neurodegenerative disease associated with mutations in the human VPS13A gene. The mechanism of ChAc pathogenesis is unclear. A simple yeast model was used to investigate the function of Vps13. Vps13, like hVps13A, is involved in vesicular protein transport, actin cytoskeleton organisation and phospholipid metabolism. A new phenotype of the vps13Δ mutant, SDS-hypersensitivity, was used to screen a yeast genomic library for multicopy suppressors. A fragment of the MYO3 gene, encoding the N-terminal part of myosin, a protein involved in the actin cytoskeleton and in endocytosis, was isolated. Myo3-N protein contains a motor head domain and a linker. The linker contains IQ motifs that mediate the binding of calmodulin, a negative regulator. Amino acid substitutions that disrupt the interaction of Myo3-N with calmodulin resulted in the loss of vps13Δ suppression. Production of Myo3-N downregulated the activity of calcineurin, a protein phosphatase regulated by calmodulin, and alleviated some defects in early endocytosis events. Importantly, EGTA, which sequesters calcium and thus downregulates calmodulin and calcineurin, was a potent suppressor of vps13Δ. We propose that Myo3-N acts by sequestering calmodulin, downregulating calcineurin and activation of Myo3, which is involved in endocytosis and in Osh2/3 dependent endoplasmic reticulum-plasma membrane contact sites. These results show that defects associated with vps13Δ could be overcome and point to a functional connection between Vps13 and calcium signalling as a possible target for chemical intervention in ChAc. Yeast ChAc models may uncover the underlying pathological mechanisms, may also serve as a platform for drug testing.

Funder

Narodowe Centrum Nauki

Biotechnology and Biological Sciences Research Council

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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