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Cholesterol metabolism in Huntington disease

Nature Reviews Neurology volume 7, pages 561–572 (2011)Cite this article

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Abstract

The CNS is rich in cholesterol, which is essential for neuronal development and survival, synapse maturation, and optimal synaptic activity. Alterations in brain cholesterol homeostasis are linked to neurodegeneration. Studies have demonstrated that Huntington disease (HD), a progressive and fatal neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin protein, is associated with changes in cellular cholesterol metabolism. Emerging evidence from human and animal studies indicates that attenuated brain sterol synthesis and accumulation of cholesterol in neuronal membranes represent two distinct mechanisms occurring in the presence of mutant huntingtin that influence neuronal survival. Increased knowledge of how changes in intraneuronal cholesterol metabolism influence the pathogenesis of HD will provide insights into the potential application of brain cholesterol regulation as a therapeutic strategy for this devastating disease.

Key Points

  • The brain is a cholesterol-rich organ, and cholesterol has a critical role in brain development, synaptogenesis, and neuronal activity and survival

  • Disturbances in brain cholesterol homeostasis are implicated in neurodegeneration

  • Attenuated plasma cholesterol levels, reduced brain cholesterol synthesis and cholesterol accumulation in neuronal plasma membranes are observed in patients with Huntington disease (HD) and in animal models of the disease

  • Multiple mechanisms are proposed to underlie cholesterol dysregulation in HD, including impaired activation of sterol regulatory element-binding protein, which regulates cholesterogenic gene expression, and reduced brain-derived neurotrophic factor signaling

  • Disturbances in cholesterol homeostasis may influence neuronal survival and susceptibility to excitotoxicity

  • Targeting of cholesterol metabolism represents a potential avenue for treatment to alleviate some neuronal impairments in HD

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Figure 1: Cholesterol metabolism and transport in the CNS.
Figure 2: Influence of mutant huntingtin on the cholesterol biosynthesis pathway.
Figure 3: Influence of mHtt on SREBP-dependent cellular cholesterol synthesis.
Figure 4: Neuronal cholesterol accumulation in the presence of mHtt.
Figure 5: Huntingtin, BDNF trafficking and neuronal cholesterol synthesis.
Figure 6: Potential cholesterol-dependent pathways influencing neuropathology in Huntington disease.

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Acknowledgements

This study was supported by grants from the Canadian Institutes of Health Research (CIHR MOP-106684 and MOP-84438).

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Authors and Affiliations

  1. Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, V5Z 4H4, BC, Canada

    Joanna M. Karasinska & Michael R. Hayden

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  1. Joanna M. Karasinska
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  2. Michael R. Hayden
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J. M. Karasinska researched data for the article and wrote the text. J. M. Karasinska and M. R. Hayden contributed equally to discussions of content, and review and editing of the manuscript before submission.

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Correspondence to Michael R. Hayden.

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Karasinska, J., Hayden, M. Cholesterol metabolism in Huntington disease. Nat Rev Neurol 7, 561–572 (2011). https://doi.org/10.1038/nrneurol.2011.132

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