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Review

V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities

by
Antonio Falace
1,*,†,
Greta Volpedo
2,†,
Marcello Scala
2,3,
Federico Zara
2,3,
Pasquale Striano
1,2,‡ and
Anna Fassio
4,5,‡
1
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
2
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy
3
Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
4
Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy
5
IRCCS, Ospedale Policlinico San Martino, 16132 Genoa, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Cells 2024, 13(17), 1441; https://doi.org/10.3390/cells13171441
Submission received: 6 July 2024 / Revised: 23 August 2024 / Accepted: 25 August 2024 / Published: 28 August 2024
(This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration)
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Abstract

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H+ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction.
Keywords: v-ATPse; lysosomal dysfunction; neurodevelopmental disorders; neurodegeneration v-ATPse; lysosomal dysfunction; neurodevelopmental disorders; neurodegeneration

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MDPI and ACS Style

Falace, A.; Volpedo, G.; Scala, M.; Zara, F.; Striano, P.; Fassio, A. V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities. Cells 2024, 13, 1441. https://doi.org/10.3390/cells13171441

AMA Style

Falace A, Volpedo G, Scala M, Zara F, Striano P, Fassio A. V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities. Cells. 2024; 13(17):1441. https://doi.org/10.3390/cells13171441

Chicago/Turabian Style

Falace, Antonio, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. 2024. "V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities" Cells 13, no. 17: 1441. https://doi.org/10.3390/cells13171441

APA Style

Falace, A., Volpedo, G., Scala, M., Zara, F., Striano, P., & Fassio, A. (2024). V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities. Cells, 13(17), 1441. https://doi.org/10.3390/cells13171441

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