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

Mohitkumar R. Gangwani; Joselyn S. Soto; Yasaman Jami-Alahmadi; Srushti Tiwari; Riki Kawaguchi; James A. Wohlschlegel; Baljit S. Khakh

Cell Reports (Jan 2023)

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

Mohitkumar R. Gangwani,
Joselyn S. Soto,
Yasaman Jami-Alahmadi,
Srushti Tiwari,
Riki Kawaguchi,
James A. Wohlschlegel,
Baljit S. Khakh

Affiliations

Mohitkumar R. Gangwani: Department of Physiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
Joselyn S. Soto: Department of Physiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
Yasaman Jami-Alahmadi: Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
Srushti Tiwari: Department of Physiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
Riki Kawaguchi: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
James A. Wohlschlegel: Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095-1751, USA
Baljit S. Khakh: Department of Physiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Neurobiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 1
p. 111953

Abstract

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Summary: 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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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