Progress in the study of Huntington's disease
A benchmark study offers new hope in the study of Huntington's disease (HD), a degenerative brain disorder that results in loss of mental and physical faculties. The findings of this large international project, headed by Ecole Polytechnique Fédérale de Lausanne, in collaboration with laboratories in the UK, New Zealand, Canada, Australia and the US, reveal that gene expression in several animal models of HD closely resembles that of human HD patients. Consequently, the researchers assert, animal models can be applied to study the disease, giving the green light for these models to be used in preclinical drug testing.
Huntington's disease is an incurable hereditary disorder. Symptoms of the disease emerge in mid-adulthood and exacerbate progressively, impairing the sufferer's ability to think, speak and walk. One in every 10 000 Europeans is affected by the fatal disease.
|HD is an incurable neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein.
HD has been traced to a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to acute motor, psychiatric, and cognitive deterioration. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This knowledge has paved the way for novel new research into the causes of neuronal death and approaches for treatment.
Likewise, the results from the international collaboration (led by Professor Ruth Luthi-Carter from Ecole Polytechnique Fédérale de Lausanne) represent a significant addition to the body of scientific knowledge on HD. The results now suggest that it is possible for potential treatments to be tested on non-human subjects, due to the marked resemblance uncovered between the molecular etiology of neurons in animal models and neurons in patients with HD.
In reaching this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons.
The team then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients.
'Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD,' says Ruth Luthi-Carter.
'It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington’s disease.'
Results of the report have been published in Human Molecular Genetics under the title, "Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage".
Ecole Polytechnique Fédérale de Lausanne
Human Molecular Genetics