HDAC inhibition improves autophagic and lysosomal function to prevent loss of subcutaneous fat in a mouse model of Cockayne syndrome

Abstract

Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the gene, affects multiple organs including skin where it manifests with hypersensitivity toward ultraviolet (UV) radiation and loss of subcutaneous fat. There is no curative treatment for CS, and its pathogenesis is only partially understood. Originally considered for its role in DNA repair, Cockayne syndrome group B (CSB) protein most likely serves additional functions. Using CSB-deficient human fibroblasts,, and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of mice to UVA radiation caused a severe skin phenotype with loss of subcutaneous fat, inflammation, and fibrosis. These changes in skin tissue were associated with an accumulation of autophagic/lysosomal proteins and reduced amounts of acetylated α-tubulin. At the cellular level, we found that CSB directly interacts with the histone deacetylase 6 (HDAC6) and the α-tubulin acetyltransferase MEC-17. Upon UVA irradiation, CSB is recruited to the centrosome where it colocalizes with dynein and HDAC6. Administration of the pan-HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) enhanced α-tubulin acetylation, improved autophagic function in CSB-deficient models from all three species, and rescued the skin phenotype in mice. HDAC inhibition may thus represent a therapeutic option for CS.

Emerging Role of the Nucleolar Stress Response in Autophagy

“…CSB-deficient cells show increased ROS production, increased mitochondrial content and accumulation of damaged mitochondria, in line with impaired mitophagy (Scheibye-Knudsen et al, 2012). Further, CSB promotes acetylation of α-tubulin (Majora et al, 2018), which is a modification involved in cargo transport along microtubules to facilitate autophagosome/autolysosome fusion and aggresome clearance (Xie et al, 2010; Li et al, 2011). CSB deficiency abrogates autophagy and results in increased number of dilated lysosomes with impaired function (Majora et al, 2018).…”

“…Further, CSB promotes acetylation of α-tubulin (Majora et al, 2018), which is a modification involved in cargo transport along microtubules to facilitate autophagosome/autolysosome fusion and aggresome clearance (Xie et al, 2010; Li et al, 2011). CSB deficiency abrogates autophagy and results in increased number of dilated lysosomes with impaired function (Majora et al, 2018). In human CS cells, translational infidelity is observed, most likely due to accumulation of error-prone ribosomes as a consequence of impaired ribosome replacement.…”

From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs

“…Another hereditary form of premature aging, Cockayne syndrome (CS), is caused by mutations in five different genes that encode proteins involved in nucleotide excision DNA repair, causing hypersensitivity to UV radiation and loss of subcutaneous fat (Majora et al , ). Across CSB ‐deficient human fibroblasts, Caenorhabditis elegans , and mice, treatment with SAHA enhanced alpha‐tubulin acetylation and improved autophagic function, and even rescued the skin phenotype observed in mice, suggesting it may provide a therapeutic option for CS (Majora et al , ). Together, these findings not only suggest that HDAC inhibitors can provide treatment for diseases of premature aging, but also provide further evidence of HDAC inhibitor efficacy as a geroprotective compound.…”

Autophagic Control of Skin Aging

“…Fibroblasts from patients deficient in Cockayne syndrome B (CSB) protein display impaired autophagy due to interaction of CSB with HDAC6 and cytoskeletal components. Importantly, the restoration of autophagic function could revert the premature aging and photosensitivity phenotype in a CSB mouse model (Majora et al, 2018). The movement of the autophagic-lysosomal components along cytoskeletal components through motor proteins was demonstrated in a study in mouse fibroblasts.…”