Giovedì Silvia, Ravanelli Margherita Maria, Parisi Barbara, Bettegazzi Barbara, Guarnieri Fabrizia Claudia
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
IRCCS, Ospedale Policlinico San Martino, Genoa, Italy.
Front Cell Neurosci. 2020 Dec 17;14:602116. doi: 10.3389/fncel.2020.602116. eCollection 2020.
Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.
自噬和内溶酶体运输在神经元发育、功能及存活过程中至关重要。这些过程确保了易于错误折叠的聚集倾向蛋白和受损细胞器（如功能失调的线粒体）被有效清除，从而维持细胞内适当的稳态。除此之外，新出现的证据表明它们参与了对保证有效神经递质释放和突触可塑性所需的突触蛋白质组的调节。沿着这一思路，调节突触小泡内吞作用和突触自噬的分子机制之间正呈现出密切的相互作用，这表明突触质量控制机制需要与神经分泌紧密耦合以确保释放准确性。自噬和内溶酶体途径的缺陷与神经元功能障碍相关，并且在阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症等其他神经退行性疾病中已有广泛报道，这些疾病具有共同特征和新出现的遗传基础。在本综述中，我们聚焦于自噬和内溶酶体系统在神经元稳态中的多种作用，并强调它们的缺陷可能如何导致上述疾病中的突触功能障碍和神经退行性变，同时讨论了探索治疗干预的最新选择。
