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

被引:3
|
作者
Falace, Antonio [1 ]
Volpedo, Greta [2 ]
Scala, Marcello [2 ,3 ]
Zara, Federico [2 ,3 ]
Striano, Pasquale [1 ,2 ]
Fassio, Anna [4 ,5 ]
机构
[1] IRCCS Ist Giannina Gaslini, Pediat Neurol & Muscular Dis Unit, I-16147 Genoa, Italy
[2] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16132 Genoa, Italy
[3] IRCCS Ist Giannina Gaslini, Med Genet Unit, I-16147 Genoa, Italy
[4] Univ Genoa, Dept Expt Med, I-16132 Genoa, Italy
[5] Osped Policlin San Martino, IRCCS, I-16132 Genoa, Italy
关键词
v-ATPse; lysosomal dysfunction; neurodevelopmental disorders; neurodegeneration; GDP/GTP EXCHANGE PROTEIN; COGNITIVE IMPAIRMENT; MENTAL-RETARDATION; PROTON PUMP; EPILEPSY; MUTATIONS; LYSOSOME; ACIDIFICATION; PARKINSONISM; ONSET;
D O I
10.3390/cells13171441
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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收藏
页数:21
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