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Volume 11
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10.3390/genes11070828
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Article

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

by
Piotr Soczewka
1,
Krzysztof Flis
1,
Déborah Tribouillard-Tanvier
2,3,
Jean-Paul di Rago
2,
Cláudia N. Santos
4,5,
Regina Menezes
4,5,
Joanna Kaminska
1 and
Teresa Zoladek
1,*
1
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106 Warsaw, Poland
2
CNRS, Institut de Biochimie et Génétique Cellulaires, Bordeaux University, CEDEX, 33077 Bordeaux, France
3
Institut National de la Santé et de la Recherche Médicale INSERM, 33077 Bordeaux, France
4
Instituto de Biologia Experimental e Tecnológica, Av. República, Qta. do Marquês, 2780-157 Oeiras, Portugal
5
CEDOC—Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Rua Câmara Pestana n° 6, 6-A Edifício CEDOC II, 1150-082 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Genes 2020, 11(7), 828; https://doi.org/10.3390/genes11070828
Submission received: 9 June 2020 / Revised: 6 July 2020 / Accepted: 17 July 2020 / Published: 21 July 2020
(This article belongs to the Special Issue Genetic Aspects of Yeast: Cell Biology, Ecology and Biotechnology)
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Abstract

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A–D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13Δ mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13Δ cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure–activity relationship and molecular mechanisms underlying the action of luteolin were characterized. The FET4 gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13Δ, pointing out the importance of iron in response to SDS stress. The growth defect of vps13Δ in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13Δ may help to better understand VPS13A–D-dependent pathogenesis and to develop novel therapeutic strategies.
Keywords: yeast model; neurodegenerative diseases; VPS13 genes; drug repurposing; luteolin; tolcapone; FET4 gene; iron; sphingolipid biosynthesis; csg2Δ yeast model; neurodegenerative diseases; VPS13 genes; drug repurposing; luteolin; tolcapone; FET4 gene; iron; sphingolipid biosynthesis; csg2Δ

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MDPI and ACS Style

Soczewka, P.; Flis, K.; Tribouillard-Tanvier, D.; di Rago, J.-P.; Santos, C.N.; Menezes, R.; Kaminska, J.; Zoladek, T. Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases. Genes 2020, 11, 828. https://doi.org/10.3390/genes11070828

AMA Style

Soczewka P, Flis K, Tribouillard-Tanvier D, di Rago J-P, Santos CN, Menezes R, Kaminska J, Zoladek T. Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases. Genes. 2020; 11(7):828. https://doi.org/10.3390/genes11070828

Chicago/Turabian Style

Soczewka, Piotr, Krzysztof Flis, Déborah Tribouillard-Tanvier, Jean-Paul di Rago, Cláudia N. Santos, Regina Menezes, Joanna Kaminska, and Teresa Zoladek. 2020. "Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases" Genes 11, no. 7: 828. https://doi.org/10.3390/genes11070828

APA Style

Soczewka, P., Flis, K., Tribouillard-Tanvier, D., di Rago, J.-P., Santos, C. N., Menezes, R., Kaminska, J., & Zoladek, T. (2020). Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases. Genes, 11(7), 828. https://doi.org/10.3390/genes11070828

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