Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging

Abstract

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.

Collagen VI in healthy and diseased nervous system

“…Recent work by our group, aimed at investigating the physiological role for ColVI in the brain, also reported ColVI expression in primary hippocampal neurons, as well as in the meninges and brain blood vessels, in the hippocampal region, and in the corpus callosum ( Box 1 ). Moreover, we demonstrated the presence of distinctive neurodegenerative traits in aged ColVI knockout ( Col6a1 −/− ) mice ( Box 2 ), pointing at a protective role for ColVI in physiological aging ( Cescon et al, 2016 ), further corroborating the concept that ColVI protects neuronal cells against age-dependent neurodegeneration. Using wild-type and Col6a1 −/− mice, we found that the COL6 genes were upregulated during aging and demonstrated that geriatric (23-month-old) ColVI-null mice displayed a higher incidence of apoptosis, higher oxidative damage and altered autophagic flux in neuronal cells compared with age-matched wild-type mice.…”

“…The Col6a1 −/− mouse model bears a targeted inactivation of the Col6a1 gene, thus preventing ColVI assembly and deposition within the ECM ( Bonaldo et al, 1998 ). The use of Col6a1 −/− mice unveiled novel aspects of ColVI biology in the CNS and PNS, as discussed in the main text ( Cheng et al, 2009 ; Chen et al, 2014 , 2015 ; Cescon et al, 2016 ). Other mouse models for ColVI-related myopathies were generated, such as those targeting the Col6a3 gene.…”

“…Using wild-type and Col6a1 −/− mice, we found that the COL6 genes were upregulated during aging and demonstrated that geriatric (23-month-old) ColVI-null mice displayed a higher incidence of apoptosis, higher oxidative damage and altered autophagic flux in neuronal cells compared with age-matched wild-type mice. The occurrence of neurodegenerative hallmarks in aged ColVI-null mice was accompanied by impaired motor coordination and spatial memory, highlighting a crucial neuroprotective role of ColVI during physiological aging ( Cescon et al, 2016 ).…”

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

“…In a separate study the loss of miR-29a was correlated with increased levels of BACE1 and amyloid-β in sporadic Alzheimer's Disease [27]. Finally, lack of collagen VI has been related to neurodegeneration in mice models [11], and its presence has been related to a neuroprotective role against β-Amyloid toxicity [13].…”

Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung

“…However, Col6a1 À/À mice do not show signs of increased inflammation, and appear to have a normal lifespan relative to wildtype mice, indicating that the condition in these mice may not be progressive and degenerative, but may be more likely a result of developmental defects. 55,56 It is possible that COL6 plays a role in chronic lung disease due to prematurity, as longitudinal cohort studies have shown early evidence of obstructive lung disease persisting into adolescence and young adulthood. 57,58 Genes with reduced expression in Col6a1 À/À lungs are significantly enriched with markers of endothelial cells, B Figure 5 Alveolar vasculature and epithelial type II (ATII) cells are reduced in Col6a1 À/À Lungs.…”