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

doi:10.1016/j.celrep.2022.111953

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

Cell Rep. 2023 Jan 31;42(1):111953. doi: 10.1016/j.celrep.2022.111953. Epub 2023 Jan 7.

Authors

Mohitkumar R Gangwani¹, Joselyn S Soto¹, Yasaman Jami-Alahmadi², Srushti Tiwari¹, Riki Kawaguchi³, James A Wohlschlegel², Baljit S Khakh⁴

Affiliations

¹ Department of Physiology, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
² Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
³ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
⁴ 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. Electronic address: bkhakh@mednet.ucla.edu.

Abstract

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.

Keywords: CP: Neuroscience; Huntington’s disease; astrocyte; huntingtin; medium spiny neuron; neurodegeneration; striatum; therapeutics; zinc finger protein.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Astrocytes / metabolism
Disease Models, Animal
Huntingtin Protein / genetics
Huntingtin Protein / metabolism
Huntington Disease* / genetics
Huntington Disease* / metabolism
Mutant Proteins / metabolism
Neurons / metabolism
Transcription Factors / metabolism
Zinc Fingers

Substances

Huntingtin Protein
Transcription Factors
Mutant Proteins

Grants and funding

R35 NS111583/NS/NINDS NIH HHS/United States