Highlights d Telomere dysfunction downregulates sirtuins in the liver in a p53-dependent manner d p53 represses sirtuins through transcriptional and posttranscriptional mechanisms d Telomere dysfunction is linked to a steep decline in NAD(+) upon additional damage d NAD(+) supplementation stabilizes telomeres and improves liver fibrosis

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Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. Kctd7 (EPM3) is a member of a large family of progressive myoclonic epilepsy (EPM) syndromes displaying a broad spectrum of clinical severity. Animal models of Kctd7-related disease are lacking, and little is known regarding how Kctd7 protein defects lead to epilepsy and cognitive dysfunction. We characterized brain Kctd7 expression patterns during development and show it is selectively enriched in specific regions as the brain matures. We further demonstrate that Kctd7-deficient mice develop seizures and locomotor defects with features similar to those observed in human KCTD7-associated disease. We also show that Kctd7 is required for Purkinje cell survival in the cerebellum and that selective degeneration of these neurons is accompanied by defects in cerebellar brain microvascular organization and patterning. Together, these results define a new model for Kctd7- associated epilepsy and identify Kctd7 as a modulator of neuron survival and excitability linked to microvascular alterations in vulnerable regions.

Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.

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