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Distinct sub-cellular autophagy impairments independent of protein aggregation in induced neurons from patients with Huntington disease

ABSTRACT: Huntington’s disease(HD)is a hereditary neurodegenerative disorder that is caused by CAGexpansionsin the huntingtin(HTT)gene. Modelling HD in the lab has proven challenging asrodent models poorly reproduce the disease process and cellular models fail to include age-dependent processescrucial tothe disease. Here we generatedinduced neurons(iNs)throughdirect reprogrammingof fibroblastfrombothHD-patients and healthy controls. This procedureresultedin the generation ofpatient-derived HD neurons that retainedage-dependentcharacteristics. We found that HD-iNsconsistentlydisplayedshorterandfewerneuritescomparted to ctrl-iNsandthat thisphenotypecould be rescuedbyCRISPRi-mediated silencingof mHTT.Proteomics analysis demonstrated an alteration in AMPK-signalling and autophagyin HD-iNs. In line with this,HD-iNs displayeda distinctalteration inautophagy activity,characterizedby areduction in thetransportoflate autophagic structuresfrom neurites tothecell-bodyand subsequent cargo degradation.These results identify a novel therapeutic targetfor HD and provides a rational for futuredevelopmentof CRISPR-based approaches to treatHD

ORGANISM(S): Homo sapiens

PROVIDER: GSE182866 | GEO | 2022/07/22

REPOSITORIES: GEO

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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.

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Distinct sub-cellular autophagy impairments independent of protein aggregation in induced neurons from patients with Huntington disease

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