Related Experiment Video
Updated: Aug 8, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Astrocytic contributions to Huntington's disease pathophysiology
Baljit S Khakh1,2, Steven A Goldman3,4
1Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Insights
Huntington's disease (HD) involves mutant huntingtin proteins affecting striatal astrocytes. Targeting these astrocytes may restore homeostasis and offer new therapeutic strategies for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene.
- Mutant huntingtin proteins (mHTT) affect various cells, with particular vulnerability in the striatum.
- Striatal astrocytes, abundant glial cells, accumulate mHTT in HD.
Purpose of the Study:
- To investigate the role of striatal astrocytes in Huntington's disease pathophysiology.
- To summarize astrocytic contributions to molecular pathology and disease phenotypes in HD models.
- To explore the potential of targeting astrocytes for therapeutic interventions in HD.
Main Methods:
- Review of studies on striatal astrocytes in HD mouse models.
- Analysis of astrocyte alterations in human HD cases.
- Examination of cellular morphology, ion/neurotransmitter homeostasis, and metabolic support in astrocytes.
Main Results:
- Striatal astrocytes exhibit dysfunction in morphology, homeostasis, and metabolic support during HD progression.
- These astrocytic dysfunctions are observed in transgenic mouse models, human cellular models, and chimeric models of HD.
- Astrocytes actively participate in and contribute to the molecular pathophysiology and phenotypes of HD.
Conclusions:
- Dysfunctional striatal astrocytes are integral to Huntington's disease pathogenesis.
- Targeting astrocyte-specific pathways holds therapeutic potential for restoring homeostasis in HD.
- Understanding glial pathology in HD can advance glial-directed therapeutics for neurodegenerative disorders.
Abstract:
Huntington's disease (HD) is a fatal, monogenic, autosomal dominant neurodegenerative disease caused by a polyglutamine-encoding CAG expansion in the huntingtin (HTT) gene that results in mutant huntingtin proteins (mHTT) in cells throughout the body. Although large parts of the central nervous system (CNS) are affected, the striatum is especially vulnerable and undergoes marked atrophy. Astrocytes are abundant within the striatum and contain mHTT in HD, as well as in mouse models of the disease. We focus on striatal astrocytes and summarize how they participate in, and contribute to, molecular pathophysiology and disease-related phenotypes in HD model mice. Where possible, reference is made to pertinent astrocyte alterations in human HD. Astrocytic dysfunctions related to cellular morphology, extracellular ion and neurotransmitter homeostasis, and metabolic support all accompany the development and progression of HD, in both transgenic mouse and human cellular and chimeric models of HD. These findings reveal the potential for the therapeutic targeting of astrocytes so as to restore synaptic as well as tissue homeostasis in HD. Elucidation of the mechanisms by which astrocytes contribute to HD pathogenesis may inform a broader understanding of the role of glial pathology in neurodegenerative disorders and, by so doing, enable new strategies of glial-directed therapeutics.
More Related Videos
08:27Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice
Published on: March 11, 2020
10:38Author Spotlight: Understanding the Impact of Pathological Proteins on Axonal Transport in Neurodegenerative Diseases
Published on: December 22, 2023
