Research ArticleCOCKAYNE SYNDROME

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

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaam7510
DOI: 10.1126/scitranslmed.aam7510

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Autophagy and adipose

Hypersensitivity to sunlight and decreased subcutaneous fat are characteristics of Cockayne syndrome, a genetic disorder of premature aging. Majora and colleagues studied the role of autophagy underlying this skin phenotype using mice with a mutation in csb, a gene that causes Cockayne syndrome. They found an accumulation of autophagy-related proteins and lysosomal dysfunction in skin from csb mutant mice exposed to ultraviolet light. Treatment with a histone deacetylase inhibitor prevented loss of subcutaneous fat and rescued autophagic/lysosomal dysfunction. Further research is necessary to determine whether histone deacetylase inhibition can resolve other features of Cockayne syndrome, such as neurodegeneration.

Abstract

Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the csb 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, Caenorhabditis elegans, and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of csbm/m 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 csbm/m mice. HDAC inhibition may thus represent a therapeutic option for CS.

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