Limanaqi Fiona, Biagioni Francesca, Gambardella Stefano, Ryskalin Larisa, Fornai Francesco
Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
IRCCS Neuromed, Pozzilli, Italy.
Front Mol Neurosci. 2018 Aug 21;11:299. doi: 10.3389/fnmol.2018.00299. eCollection 2018.
Autophagy (ATG) and the Ubiquitin Proteasome (UP) are the main clearing systems of eukaryotic cells, in that being ultimately involved in degrading damaged and potentially harmful cytoplasmic substrates. Emerging evidence implicates that, in addition to their classic catalytic function in the cytosol, autophagy and the proteasome act as modulators of neurotransmission, inasmuch as they orchestrate degradation and turnover of synaptic vesicles (SVs) and related proteins. These findings are now defining a novel synaptic scenario, where clearing systems and secretory pathways may be considered as a single system, which senses alterations in quality and distribution (in time, amount and place) of both synaptic proteins and neurotransmitters. In line with this, in the present manuscript we focus on evidence showing that, a dysregulation of secretory and trafficking pathways is quite constant in the presence of an impairment of autophagy-lysosomal machinery, which eventually precipitates synaptic dysfunction. Such a dual effect appears not to be just incidental but it rather represents the natural evolution of archaic cell compartments. While discussing these issues, we pose a special emphasis on the role of autophagy upon dopamine (DA) neurotransmission, which is early affected in several neurological and psychiatric disorders. In detail, we discuss how autophagy is engaged not only in removing potentially dangerous proteins, which can interfere with the mechanisms of DA release, but also the fate of synaptic DA vesicles thus surveilling DA neurotransmission. These concepts contribute to shed light on early mechanisms underlying intersection of autophagy with DA-related synaptic disorders.
自噬（ATG）和泛素蛋白酶体（UP）是真核细胞的主要清除系统，最终参与降解受损的和潜在有害的细胞质底物。新出现的证据表明，除了在细胞质中具有经典的催化功能外，自噬和蛋白酶体还作为神经传递的调节因子，因为它们协调突触小泡（SVs）和相关蛋白的降解与周转。这些发现正在定义一种新的突触情况，即清除系统和分泌途径可被视为一个单一系统，该系统能感知突触蛋白和神经递质在质量和分布（时间、数量和位置）上的变化。与此一致，在本手稿中，我们关注的证据表明，在自噬 - 溶酶体机制受损的情况下，分泌和运输途径的失调相当常见，这最终会导致突触功能障碍。这种双重作用似乎并非偶然，而是古老细胞区室自然进化的结果。在讨论这些问题时，我们特别强调自噬对多巴胺（DA）神经传递的作用，多巴胺神经传递在几种神经和精神疾病中会早期受到影响。详细地说，我们讨论自噬不仅如何参与清除可能干扰DA释放机制的潜在危险蛋白，还参与突触DA小泡的命运，从而监测DA神经传递。这些概念有助于阐明自噬与DA相关突触疾病交叉的早期机制。
