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Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

ABSTRACT: We used cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and experimentally evaluated the consequences of neuronal and astrocytic mHTT lowering on HD pathophysiology using cell-type specific RNA-seq

ORGANISM(S): Mus musculus

PROVIDER: GSE211891 | GEO | 2022/12/15

REPOSITORIES: GEO

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Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

Project description:Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) that results in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts in diverse cells of the body, including striatal neurons and astrocytes. The relative contributions of neurons and astrocytes to disease pathogenesis are unknown for HD and other neurodegenerative diseases. This is a critical issue to address since it has been proposed that neuronal loss in HD and other major neurodegenerative diseases is downstream of astrocytic dysfunction that drives neuronal death. Moreover, astrocyte-to-neuron conversion is considered a promising approach in HD and other neurodegenerative diseases with little reported detriment with regards to normal astrocytic physiological functions, which are varied and extensive in health and disease. Thus, astrocytes are considered both causative and also largely replaceable in neurodegeneration, and their basic contributions to disease pathophysiology relative to neurons remain undefined in vivo. We used genetically encoded and cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and molecularly dissected neuronal and astrocytic influences on HD pathophysiology at molecular, cellular, and behavioral levels. We found that the major disease drivers were in fact neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were downstream of greater neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling. We thus dissected the cell autonomous and non-cell autonomous mechanistic and causal contributions of both neurons and astrocytes to a complex neurodegenerative disease in vivo with wider implications for rescue and repair strategies.

2022-12-15 | PXD030021 | Pride

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Neuronal and astrocytic contributions to Huntington's disease dissected with zinc finger protein transcriptional repressors.

Project description:Huntington's disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) resulting in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts, including in striatal neurons and astrocytes. It is unknown whether pathophysiology in vivo can be attenuated by lowering mHTT in either cell type throughout the brain, and the relative contributions of neurons and astrocytes to HD remain undefined. We use zinc finger protein (ZFP) transcriptional repressors to cell-selectively lower mHTT in vivo. Astrocytes display loss of essential functions such as cholesterol metabolism that are partly driven by greater neuronal dysfunctions, which encompass neuromodulation, synaptic, and intracellular signaling pathways. Using transcriptomics, proteomics, electrophysiology, and behavior, we dissect neuronal and astrocytic contributions to HD pathophysiology. Remarkably, brain-wide delivery of neuronal ZFPs results in strong mHTT lowering, rescue of HD-associated behavioral and molecular phenotypes, and significant extension of lifespan, findings that support translational development.

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