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Huntington's Disease: Unraveling the Pathophysiological Cascade Behind a Singular Gene Defect

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Abstract:

Huntington's disease (HD), an autosomal dominantly inherited disease, belongs to a group of neurodegenerative disorders, which share the same genetic defect, i.e., a CAG triplet expansion that is translated into polyglutamine chains within different proteins. Although HD is caused by a singular gene defect, this disease shows a high variability in age of onset and in its clinical manifestations, which include characteristic motor, cognitive, and psychiatric symptoms. This variability can only partly be explained by changes in CAG length. While some other rare neurodegenerative diseases share some of the clinical phenotype with HD, some perplexing phenocopies of HD called “HD‐like diseases” have been identified recently, which are related to different gene defects. The key step in the molecular pathology is a conformational change in the expanded polyglutamine above a certain length threshold, which leads to formation of β‐strands and polyglutamine aggregation. As a histopathological hallmark, intranuclear huntingtin‐positive aggregates have been identified, making HD another neurodegenerative disease, with the presence of insoluble protein aggregates, like Alzheimer's or Parkinson's disease. Furthermore, key steps in molecular pathology include early changes in transcriptional regulation. Numerous transgenic mouse, fly, and in vitro cellular models help us to elucidate disease mechanism and evaluate therapeutic strategies. This allows more specific therapeutic interventions in the near future, in this model disease, for hereditary neurodegenerative disorders.

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Abbreviations

APOE:

apolipoprotein E

BDNF:

brain‐derived neurotrophic factor

CBP:

CREB‐binding protein

DRPLA:

dentato‐rubro‐pallido‐luysian atrophy

HARP:

hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration

HD:

Huntington's disease

Hdh:

mouse HD gene homologue

IT15:

interesting transcript 15, name of the HD gene on chromosome 4

NAA:

N‐acetylaspartate

NMDA:

N‐methyl‐d‐aspartate

PEG:

percutaneous endoscopic gastrostomy

SAHA:

suberoylanilide hydroxamic acid

SCA:

spinocerebellar atrophy

UTR:

untranslated region

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Authors
  1. C. M. Kosinski
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  2. B. Landwehrmeyer
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  3. A. Ludolph
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, New York, 10962, Orangeburg, USA

    Abel Lajtha (Director) (Director)

  2. Technion‐Rappaport Family Faculty of Medicine, Efron St., POBox 9697, 31096, Haifa, Israel

    Moussa B. H. Youdim (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research) (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research)

  3. Clinic and Policlinic of Psychiatry and Psychotherapy Dept. Clinical Neurochemistry, University of Würzburg, Füchsleinstr. 15, 97080, Würzburg, Germany

    Peter Riederer

  4. Eve Topf Center for Neurodegenerative Diseases Research and Dept. of Pharmacology, Faculty of Medicine Technion, Efron St., P.O.B. 9697, 31096, Haifa, Israel

    Sylvia A. Mandel

  5. Department of Neurosciences, University of Padova Medical School, Via Giustiniani 5, 35128, Padova, Italy

    Leontino Battistin

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Kosinski, C.M., Landwehrmeyer, B., Ludolph, A. (2007). Huntington's Disease: Unraveling the Pathophysiological Cascade Behind a Singular Gene Defect. In: Lajtha, A., Youdim, M.B.H., Riederer, P., Mandel, S.A., Battistin, L. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30377-2_11

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