Abstract
Autophagic decline is considered a hallmark of ageing. The activity of this intracytoplasmic degradation pathway decreases with age in many tissues and autophagy induction ameliorates ageing in many organisms, including mice. Autophagy is a critical protective pathway in neurons and ageing is the primary risk factor for common neurodegenerative diseases. Here, we describe that autophagosome biogenesis declines with age in mouse brains and that this correlates with increased expression of the SORBS3 gene (encoding vinexin) in older mouse and human brain tissue. We characterise vinexin as a negative regulator of autophagy. SORBS3 knockdown increases F-actin structures, which compete with YAP/TAZ for binding to their negative regulators, angiomotins, in the cytosol. This promotes YAP/TAZ translocation into the nucleus, thereby increasing YAP/TAZ transcriptional activity and autophagy. Our data therefore suggest brain autophagy decreases with age in mammals and that this is likely, in part, mediated by increasing levels of vinexin.
Highlights
Macroautophagy is a highly conserved mechanism for maintaining cellular homoeostasis, which functions by trafficking cytoplasmic material for enzymatic degradation in the lysosome
To confirm the relationship between vinexin-regulated autophagy and actin-related YAP/TAZ target genes, we examined MLC2, MYH10, MYH9, MYH14, ACTN1 and ACTB mRNA expression by RTqPCR in siSORBS3 treated HeLa cells. mRNA expression of these genes, known to function downstream to YAP/TAZ in autophagosome biogenesis [10], was significantly increased in HeLa cells treated with siSORBS3 (Fig. 6b)
Vinexin was previously identified as a candidate autophagy regulator from a genome-wide image-based siRNA screen that suggested siSORBS3 treatment increased autophagosome numbers due to decreased lysosomal processing, implying compromised autophagic flux [45]
Summary
Macroautophagy (hereafter referred to as autophagy) is a highly conserved mechanism for maintaining cellular homoeostasis, which functions by trafficking cytoplasmic material for enzymatic degradation in the lysosome. Autophagic decline is especially relevant to neurons, as post-mitotic cells are not able to segregate dysfunctional proteins and organelles from daughter cells using mitosis [7], which results in an increased reliance on autophagy to preserve cytoplasmic homeostasis Consistent with this observation, dysfunctional autophagy is implicated in common, age-related neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease [8]. We show SORBS3 mRNA expression increases with age in mouse and human brain tissue This corresponds to fewer autophagic vesicles in cerebral cortex samples from aged mice, as well as reduced mRNA expression of actin-related genes known to function in autophagosome biogenesis (MLC2 and MYH10) [10] in older mouse and human brain tissue. Our data suggest increased SORBS3 expression in ageing brains contributes to autophagic decline in mammalian brain ageing
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