TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons
Sara Pepe,
Davide Aprile,
Enrico Castroflorio,
Antonella Marte,
Simone Giubbolini,
Samir Hopestone,
Anna Parsons,
Tânia Soares,
Fabio Benfenati,
Peter L. Oliver,
Anna Fassio
Affiliations
Sara Pepe
Department of Experimental Medicine, University of Genova, Viale Benedetto XV/3, 16132 Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
Davide Aprile
Department of Experimental Medicine, University of Genova, Viale Benedetto XV/3, 16132 Genoa, Italy; Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy
Enrico Castroflorio
MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK
Antonella Marte
Department of Experimental Medicine, University of Genova, Viale Benedetto XV/3, 16132 Genoa, Italy
Simone Giubbolini
Department of Experimental Medicine, University of Genova, Viale Benedetto XV/3, 16132 Genoa, Italy
Samir Hopestone
MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK
Anna Parsons
MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK
Tânia Soares
MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK
Fabio Benfenati
IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genoa, Italy
Peter L. Oliver
MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK
Anna Fassio
Department of Experimental Medicine, University of Genova, Viale Benedetto XV/3, 16132 Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Corresponding author
Summary: The vacuolar ATPase (v-ATPase) is essential for acidification of intracellular organelles, including synaptic vesicles. Its activity is controlled by cycles of association and dissociation of the ATP hydrolysis (V1) and proton transport (V0) multi-protein subunits. Mutations in genes coding for both v-ATPase subunits and TBC1D24 cause neurodevelopmental disorders with overlapping syndromes; therefore, it is important to investigate their potentially interrelated functions. Here, we reveal that TBC1D24 interacts with the v-ATPase in the brain. Using a constitutive Tbc1d24 knockout mouse model, we observed accumulation of lysosomes and non-degraded lipid materials in neuronal tissue. In Tbc1d24 knockout neurons, we detected V1 mis-localization with increased pH at endo-lysosomal compartments and autophagy impairment. Furthermore, synaptic vesicles endocytosis and reacidification were impaired. Thus, we demonstrate that TBC1D24 is a positive regulator of v-ATPase activity in neurons suggesting that alteration of pH homeostasis could underlie disorders associated with TBC1D24 and the v-ATPase.
