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Huntington’s Disease: Molecular Pathogenesis and New Therapeutic Perspectives

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Abstract

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder with a clinical spectrum that includes chorea, incoordination, cognitive decline, and behavioral difficulties. The underlying genetic defect responsible for the disease is the expansion of a CAG repeat in the huntingtin (HTT) gene. This repeat is unstable and its length is inversely correlated with the age at onset of the disease. Despite its widespread distribution, mutant HTT causes neurodegeneration, which occurs preferentially in the striatum and deeper layers of the cortex. Mechanisms implicated in HD include those relevant to DNA repair, transcriptional and translational modulation of expanded trinucleotide repeats (including somatic expansion), mitochondria and energy homeostasis, vesicular trafficking dynamics, oligomerization of mHTT (chaperone biology), autophagy, epigenetic mechanisms, and synaptic signaling. Notably, not all the effects of mutant HTT are cell autonomous. The present review focuses on the molecular pathogenesis of HD and the current state of therapeutic development for the treatment of HD. We review the preclinical and clinical development molecular therapies targeting HTT expression and the modulation of biological mechanisms thought to contribute to disease pathogenesis via novel therapeutic agents.

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Authors and Affiliations

  1. National Center for Medical Genetics, National Agency of Laboratories and Health Institutes of Argentina (ANLIS) Dr. Carlos G. Malbrán, Av. Vélez Sarsfield 563, Buenos Aires, 1281, Argentina

    Claudia Perandones

  2. CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 100, Los Angeles, CA, 90045, USA

    Ignacio Muñoz-Sanjuan

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  1. Claudia Perandones
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  2. Ignacio Muñoz-Sanjuan
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Correspondence to Ignacio Muñoz-Sanjuan .

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Editors and Affiliations

  1. Parkinson Disease and Movement Disorders Program and Neurology Department, Hospital de Clínicas, José de San Martín, Buenos Aires, Argentina

    Federico E. Micheli

  2. Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, Michigan, USA

    Peter A. LeWitt

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Perandones, C., Muñoz-Sanjuan, I. (2014). Huntington’s Disease: Molecular Pathogenesis and New Therapeutic Perspectives. In: Micheli, F., LeWitt, P. (eds) Chorea. Springer, London. https://doi.org/10.1007/978-1-4471-6455-5_6

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  • DOI: https://doi.org/10.1007/978-1-4471-6455-5_6

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