Research ArticleHuntington’s Disease

Astrocyte molecular signatures in Huntington’s disease

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Science Translational Medicine  16 Oct 2019:
Vol. 11, Issue 514, eaaw8546
DOI: 10.1126/scitranslmed.aaw8546

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A shared signature

Huntington’s disease is a neurodegenerative disorder caused by a dominant mutation in the HTT gene, resulting in production of mutant huntingtin protein (mHTT). Deletion of mHTT specifically from astrocytes slowed disease progression. Now, Diaz-Castro et al. determined astrocyte gene and protein expression in patients with HD and mouse models. They identified a core signature of 62 genes whose expression was altered by mHTT expression in mice and humans. The genes were associated with basic astrocytic functions. Lowering mHTT in a mouse model restored normal expression in 61 of the 62 genes. The results pave the way for the discovery of possible therapeutic targets for treating HD.

Abstract

Astrocytes are implicated in neurodegenerative disorders and may contribute to striatal neuron loss or dysfunction in Huntington’s disease (HD). Here, we assessed striatal astrocyte gene and protein signatures in two HD mouse models at three stages and compared our results to human HD data at four clinical grades and to mice exhibiting polyglutamine length–dependent pathology. We found disease-model and stage-specific alterations and discovered a core disease-associated astrocyte molecular signature comprising 62 genes that were conserved between mice and humans. Our results show little evidence of neurotoxic A1 astrocytes that have been proposed to be causal for neuronal death in neurodegenerative disorders such as HD. Furthermore, 61 of the 62-core gene expression changes within astrocytes were reversed in a HD mouse model by lowering astrocyte mutant huntingtin protein (mHTT) expression using zinc finger protein (ZFP) transcriptional repressors. Our findings indicate that HD astrocytes progressively lose essential normal functions, some of which can be remedied by lowering mHTT. The data have implications for neurodegenerative disease rescue and repair strategies as well as specific therapeutic relevance for mHTT reduction and contribute to a better understanding of fundamental astrocyte biology and its contributions to disease.

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