Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
Cells. 2024 Aug 28;13(17):1441. doi: 10.3390/cells13171441.
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.
液泡型 ATP 酶（v-ATPase）是一种多聚体蛋白复合物，调节跨膜和细胞内细胞器的 H+运输。分解代谢过程，如内吞降解和自噬，严格依赖溶酶体中 v-ATPase 依赖性腔内酸化。v-ATPase 复合物在大脑中表达水平较高，其功能障碍会触发神经元功能障碍和神经退行性变。由于其有丝分裂后特性以及高度特化的功能和形态，神经元对溶酶体稳态失调表现出独特的易感性。编码组成 v-ATPase 或 v-ATPase 相关蛋白的亚基的基因突变会损害动物模型中的大脑发育和突触功能，并导致人类遗传疾病，如脑病、癫痫，以及神经发育和退行性疾病。本综述介绍了将 v-ATPase 亚基和辅助蛋白与各种脑疾病联系起来的遗传和功能证据，从早发性发育性癫痫性脑病到神经退行性疾病。我们强调了最新出现的旨在减轻与 v-ATPase 功能障碍相关的溶酶体缺陷的治疗策略。
