Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, USA.
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, Paris, France; Groupe Hospitalier Universitaire Paris Psychiatrie & Neurosciences, Paris, France.
J Biol Chem. 2024 Sep;300(9):107603. doi: 10.1016/j.jbc.2024.107603. Epub 2024 Jul 25.
Neurodegenerative diseases are characterized by progressive dysfunction and loss of specific sets of neurons. While extensive research has focused on elucidating the genetic and epigenetic factors and molecular mechanisms underlying these disorders, emerging evidence highlights the critical role of secretion in the pathogenesis, possibly even onset, and progression of neurodegenerative diseases, suggesting the occurrence of non-cell-autonomous mechanisms. Secretion is a fundamental process that regulates intercellular communication, supports cellular homeostasis, and orchestrates various physiological functions in the body. Defective secretion can impair the release of neurotransmitters and other signaling molecules, disrupting synaptic transmission and compromising neuronal survival. It can also contribute to the accumulation, misfolding, and aggregation of disease-associated proteins, leading to neurotoxicity and neuronal dysfunction. In this review, we discuss the implications of defective secretion in the context of Parkinson's disease, emphasizing its role in protein aggregation, synaptic dysfunction, extracellular vesicle secretion, and neuroinflammation. We propose a multiple-hit model whereby protein accumulation and secretory defects must be combined for the onset and progression of the disease.
神经退行性疾病的特征是特定神经元群的进行性功能障碍和丧失。虽然大量研究集中在阐明这些疾病的遗传和表观遗传因素以及分子机制，但新出现的证据强调了分泌在发病机制中的关键作用，甚至可能在发病和疾病进展中发挥作用，提示存在非细胞自主机制。分泌是一种调节细胞间通讯、支持细胞内稳态和协调体内各种生理功能的基本过程。分泌缺陷会损害神经递质和其他信号分子的释放，破坏突触传递并损害神经元存活。它还可能导致与疾病相关的蛋白质的积累、错误折叠和聚集，导致神经毒性和神经元功能障碍。在这篇综述中，我们讨论了分泌缺陷在帕金森病中的意义，强调了其在蛋白质聚集、突触功能障碍、细胞外囊泡分泌和神经炎症中的作用。我们提出了一个多重打击模型，即只有当蛋白质积累和分泌缺陷相结合时，疾病才会发作和进展。
