Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study

• Published in: Journal of neuropathology and experimental neurology Vol. 76; no. 7; pp. 578 - 584
• Main Authors: Kim, Catherine D., Reed, Ryan E., Juncker, Meredith A., Fang, Zhide, Desai, Shyamal D.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2017; by American Association of Neuropathologists, Inc
• Subjects: Animals; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia - pathology; Ataxia Telangiectasia Mutated Proteins - deficiency; Ataxia Telangiectasia Mutated Proteins - genetics; Autophagy - genetics; Autophagy - radiation effects; Cerebellum - metabolism; Cerebellum - radiation effects; Cytokines - metabolism; Disease Models, Animal; Gene Expression Regulation - genetics; Gene Expression Regulation - radiation effects; Genotype; Mice; Mice, Knockout; Microtubule-Associated Proteins - metabolism; Mutation - genetics; Organ Culture Techniques; Ubiquitination - genetics; Ubiquitination - radiation effects; Ubiquitins - metabolism; Ultraviolet Rays; Ubiquitin; Proteinopathy; Genotoxic stress; Ataxia telangiectasia; ISG15; Autophagy; Organotypic cerebellar culture model
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/nlx038

Abstract Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent protein degradation, leading to activation of basal autophagy as a compensatory mechanism for protein turnover in A-T cells. Also, genotoxic stress (ultraviolet [UV] radiation) deregulates autophagy and induces aberrant degradation of ubiquitylated proteins in A-T cells. In the current study, we show that, as in A-T cells, ISG15 protein expression is elevated in cerebellums and various other tissues obtained from Atm-compromised mice in an Atm-allele-dependent manner (Atm+/+  < Atm+/ − < Atm−/− ). Notably, in cerebellums, the brain part primarily affected in A-T, levels of ISG15 were significantly greater (3-fold higher) than cerebrums obtained from the same set of mice. Moreover, as in A-T cell culture, UV induces aberrant degradation of ubiquitylated proteins and autophagy in Atm-deficient, but not in Atm-proficient, cerebellar brain slices grown in culture. Thus, the ex vivo organotypic A-T mouse brain culture model mimics that of an A-T human cell culture model and could be useful for studying the role of ISG15-dependent proteinopathy in cerebellar neurodegeneration, a hallmark of A-T in humans.