Biophysical Aspects of Neurodegenerative and Neurodevelopmental Disorders Involving Endo-/Lysosomal CLC Cl−/H+ Antiporters

Author:

Coppola Maria Antonietta12,Tettey-Matey Abraham1ORCID,Imbrici Paola2ORCID,Gavazzo Paola1,Liantonio Antonella2,Pusch Michael13ORCID

Affiliation:

1. Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 16149 Genova, Italy

2. Department of Pharmacy–Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy

3. RAISE Ecosystem, 16149 Genova, Italy

Abstract

Endosomes and lysosomes are intracellular vesicular organelles with important roles in cell functions such as protein homeostasis, clearance of extracellular material, and autophagy. Endolysosomes are characterized by an acidic luminal pH that is critical for proper function. Five members of the gene family of voltage-gated ChLoride Channels (CLC proteins) are localized to endolysosomal membranes, carrying out anion/proton exchange activity and thereby regulating pH and chloride concentration. Mutations in these vesicular CLCs cause global developmental delay, intellectual disability, various psychiatric conditions, lysosomal storage diseases, and neurodegeneration, resulting in severe pathologies or even death. Currently, there is no cure for any of these diseases. Here, we review the various diseases in which these proteins are involved and discuss the peculiar biophysical properties of the WT transporter and how these properties are altered in specific neurodegenerative and neurodevelopmental disorders.

Funder

European Union—NextGenerationEU (Missione 4 Componente 2, “Dalla ricerca all’impresa”, Innovation Ecosystem RAISE “Robotics and AI for Socio-economic Empowerment”

Fondazione AIRC per la Ricerca sul Cancro

PRIN-MIUR 2017

Fondazione Telethon

Fondazione Telethon/Cariplo

Publisher

MDPI AG

Subject

Paleontology,Space and Planetary Science,General Biochemistry, Genetics and Molecular Biology,Ecology, Evolution, Behavior and Systematics

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