Yeast as a Model to Find New Drugs and Drug Targets for VPS13-Dependent Neurodegenerative Diseases

Abstract

Mutations in human VPS13A-D genes result in rare neurological diseases, including chorea-acanthocytosis. The pathogenesis of these diseases is poorly understood, and no effective treatment is available. As VPS13 genes are evolutionarily conserved, the effects of the pathogenic mutations could be studied in model organisms, including yeast, where one VPS13 gene is present. In this review, we summarize advancements obtained using yeast. In recent studies, vps13Δ and vps13-I2749 yeast mutants, which are models of chorea-acanthocytosis, were used to screen for multicopy and chemical suppressors. Two of the suppressors, a fragment of the MYO3 and RCN2 genes, act by downregulating calcineurin activity. In addition, vps13Δ suppression was achieved by using calcineurin inhibitors. The other group of multicopy suppressors were genes: FET4, encoding iron transporter, and CTR1, CTR3 and CCC2, encoding copper transporters. Mechanisms of their suppression rely on causing an increase in the intracellular iron content. Moreover, among the identified chemical suppressors were copper ionophores, which require a functional iron uptake system for activity, and flavonoids, which bind iron. These findings point at areas for further investigation in a higher eukaryotic model of VPS13-related diseases and to new therapeutic targets: calcium signalling and copper and iron homeostasis. Furthermore, the identified drugs are interesting candidates for drug repurposing for these diseases.

Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae

“…This method is useful not only for mitochondrial diseases, as described in the present review, but is also very versatile and lends itself to being easily adapted to other contexts. For example, an adapted drug drop test based on the addition of glucose and SDS to the solid medium instead of a non-fermentable carbon source was used to find new compounds and drug targets for VPS13-dependent neurodegenerative diseases (reviewed by [ 24 ]), allowing the identification of calcineurin inhibitors [ 249 ], flavonoids [ 250 ], and copper ionophores [ 251 ] to suppress the vps13Δ phenotype. Binieda and colleagues exploited yeast to perform a drug screening to identify compounds active against the Charcot Marie Tooth-GDAP1 model; in particular, an adapted drug drop test using a Ca 2+ -containing medium on the csg2Δ mutant allowed the identification of two active compounds [ 25 ].…”

“…The drug drop test was also exploited to identify molecules to treat pathologies different from mitochondrial ones, adapting the growth conditions for each specific mutant phenotype. For example, yeast was successfully used to identify compounds for VPS13-dependent neurodegenerative diseases and GDAP1-dependent Charcot Marie Tooth (reviewed in [ 24 ]) [ 25 ].…”

Chorea-echinocytosis caused by two novel compound heterozygous mutations in the VPS13A gene: a case report and literature review

“…The gold standard for the diagnosis of ChAc is genetic testing [2,3], VPS13 is currently a known causative gene [4]. Mutations in the four human VPS13 proteins (VPS13A, VPS13B, VPS13C, VPS13D) are etiological factors for ChAC, Cohen syndrome, early-onset Parkinson's disease and spastic ataxia, respectively [5]. Therefore, ChAc is also called "VPS13A disease" considering its genetic etiology [6].…”

Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0

“…Studies are presented on the mutations in IGHMBP2 , which cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) [ 2 ], and in the four VPS13 genes ( VPS13A–D ) that cause in chorea-acanthocytosis (recently renamed VPS13A disease [ 3 ], Cohen syndrome, early-onset Parkinson’s disease, and spastic ataxia/paraplegia, respectively [ 4 ]. Additionally, some studies focus on the identification of Vps13 protein localization determinants, and a review summarizes the studies showing new phenotypes of the vps13 ∆ mutant and research that aims to identify potential therapies [ 5 ]. Moreover, a review on α-arrestins is included in this collection.…”

“…These studies describe the results of yeast screens for multicopy and chemical suppressors, which point to areas for further research using other higher eukaryotic models of diseases associated with the absence of functional individual VPS13 proteins, as well as new therapeutic targets, such as calcium signaling and copper and iron homeostasis. Moreover, the identified pharmaceuticals have the potential to be repurposed for these diseases [ 5 ].…”