Cescon Matilde, Chen Peiwen, Castagnaro Silvia, Gregorio Ilaria, Bonaldo Paolo
Department of Molecular Medicine, University of Padova, I-35131 Padova, Italy.
Aging (Albany NY). 2016 May;8(5):1083-101. doi: 10.18632/aging.100924.
Collagen VI is an extracellular matrix (ECM) protein with a broad distribution in different tissues and mostly deposited at the close periphery of the cell surface. Previous studies revealed that collagen VI protects neurons from the toxicity of amyloid-βpeptides and from UV-induced damage. However, the physiological role of this protein in the central nervous system (CNS) remains unknown. Here, we established primary neural cultures from murine cortex and hippocampus, and carried out in vitro and in vivo studies in wild-type and collagen VI null (Col6a1-/-) mice. Col6a1-/- neural cultures displayed an increased incidence of spontaneous apoptosis and higher vulnerability to oxidative stress, accompanied by altered regulation of autophagy with increased p62 protein levels and decreased LC3 lipidation. Analysis of brain sections confirmed increased apoptosis and abnormal regulation of autophagy in the CNS of collagen VI-deficient animals. To investigate the in vivo physiological consequences of these CNS defects, we carried out functional studies and found that motor and memory task performances were impaired in aged Col6a1-/-mice. These findings indicate that lack of collagen VI leads to spontaneous apoptosis and defective autophagy in neural cells, and point at a protective role for this ECM protein in the CNS during physiological aging.
胶原蛋白VI是一种细胞外基质（ECM）蛋白，在不同组织中广泛分布，主要沉积在细胞表面的紧邻周边区域。先前的研究表明，胶原蛋白VI可保护神经元免受淀粉样β肽的毒性以及紫外线诱导的损伤。然而，这种蛋白在中枢神经系统（CNS）中的生理作用仍然未知。在此，我们从小鼠皮质和海马体建立了原代神经培养物，并在野生型和胶原蛋白VI基因敲除（Col6a1-/-）小鼠中进行了体外和体内研究。Col6a1-/-神经培养物显示出自发性凋亡发生率增加以及对氧化应激的更高易感性，同时伴随着自噬调节的改变，p62蛋白水平升高，LC3脂化降低。脑切片分析证实胶原蛋白VI缺陷动物的中枢神经系统中凋亡增加且自噬调节异常。为了研究这些中枢神经系统缺陷的体内生理后果，我们进行了功能研究，发现老年Col6a1-/-小鼠的运动和记忆任务表现受损。这些发现表明，胶原蛋白VI的缺乏会导致神经细胞中的自发性凋亡和自噬缺陷，并指出这种细胞外基质蛋白在生理衰老过程中对中枢神经系统具有保护作用。
