Esposito Alessandro, Pepe Sara, Cerullo Maria Sabina, Cortese Katia, Semini Hanako Tsushima, Giovedì Silvia, Guerrini Renzo, Benfenati Fabio, Falace Antonio, Fassio Anna
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
IRCCS, Ospedale Policlinico San Martino, Genoa, Italy.
Acta Physiol (Oxf). 2024 Aug;240(8):e14186. doi: 10.1111/apha.14186. Epub 2024 Jun 5.
Understanding the physiological role of ATP6V1A, a component of the cytosolic V domain of the proton pump vacuolar ATPase, in regulating neuronal development and function.
Modeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy.
Atp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V subunits, that leads to impairment of lysosomal pH-regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons.
These data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties.
了解质子泵液泡ATP酶胞质V结构域的一个组成部分ATP6V1A在调节神经元发育和功能中的生理作用。
对原代小鼠海马神经元中Atp6v1a的功能丧失进行建模，并通过免疫成像、电生理记录和电子显微镜研究神经元形态和功能。
Atp6v1a缺失影响神经突伸长、稳定以及兴奋性突触的功能，并阻止可塑性诱导时的突触重排。这些表型是由于V亚基的整体表达下降，导致溶酶体pH调节受损和自噬进程受阻，神经元胞体出现异常溶酶体积累，突触小体出现大液泡。
这些数据表明ATP6V1A在监测突触完整性和可塑性方面具有生理作用，并突出了ATP6V1A缺失在与神经发育和神经退行性疾病相关的突触功能改变中的病理生理意义。数据进一步支持了溶酶体功能和自噬通量在维持适当突触连接和适应性神经元特性方面的关键作用。
