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The molecular biology of Huntington's disease
L W Ho1, J Carmichael, J Swartz
1Department of Medical Genetics, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute of Medical Research, Addenbrooke's Hospital.
Insights
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene. Research using animal and cellular models enhances understanding of HD pathogenesis and polyglutamine diseases.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder.
- It is characterized by progressive dementia, psychiatric symptoms, and motor dysfunction.
- HD results from expanded CAG repeats in the huntingtin gene, leading to polyglutamine tracts.
Purpose of the Study:
- To review the epidemiology, clinical features, neuropathology, and genetics of HD.
- To examine findings from animal and cellular models.
- To evaluate how these models advance understanding of HD pathogenesis and other polyglutamine diseases.
Main Methods:
- Literature review of HD epidemiology, clinical features, neuropathology, and genetics.
- Analysis of findings from animal and cellular models of HD.
- Evaluation of the contribution of these models to understanding disease pathogenesis.
Main Results:
- Selective striatal and cortical neuronal death is observed in HD.
- The mutation likely confers a deleterious gain of function to the huntingtin protein.
- Neuronal intranuclear inclusions and proposed mechanisms like excitotoxicity, oxidative stress, and apoptosis contribute to neuropathology.
Conclusions:
- Significant progress has been made in understanding HD and other polyglutamine diseases.
- Unresolved issues include the role of inclusions, mechanisms of neuronal death, and disease onset.
- Further research is needed to develop novel therapeutic strategies.
Background:
Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).
Methods:
This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.
Results:
Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.
Conclusions:
Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.