Editors' ChoiceNeurodegenerative Disease

Detecting mutant huntingtin protein in HD patients

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Science Translational Medicine  15 Jul 2015:
Vol. 7, Issue 296, pp. 296ec118
DOI: 10.1126/scitranslmed.aac8559

Huntington’s disease (HD) is a progressive neurodegenerative disorder that leads to the loss of coordinated muscle movement and a decline in mental capacity, resulting in dementia. Symptoms typically become noticeable between the ages of 35 and 44 years. Tragically, although genetic testing can identify those individuals who will ultimately be affected by HD, there are no treatments to slow or reverse disease progression. HD results from an autosomal dominant mutation in the huntingtin gene whereby a cytosine-adenine-guanine (CAG) trinucleotide repeat leads to an expanded polyglutamine tract, resulting in the production of a mutant huntingtin protein with aberrant folding properties that is toxic to specific subtypes of neurons.

Now, Tan et al. report the development of a cell-based assay that can accurately identify mutant huntingtin protein in the cerebrospinal fluid of HD patients. They demonstrate that mutant huntingtin protein seeds prion-like protein propagation in their assay such that when they tested blinded samples, their seeding assay clearly distinguished HD subjects from healthy controls and from non-HD patients with dementia. This elegant assay is straightforward and potentially scalable, making it a viable assay to be tested further for use as a potential biomarker of HD. What remains to be shown is how sensitively this seeding assay correlates with patient symptom onset and severity. As there is growing evidence indicating that the more common neurodegenerative diseases, notably Alzheimer’s and Parkinson’s diseases, are also caused by aggregation of peptides or proteins such as Aβ, tau, and α-synuclein, it is possible that this assay could be adopted for clinical application across a spectrum of neurodegenerative disorders.

Applied to an automated high-throughput drug-screening platform, this assay could be used to screen hundreds of thousands of compounds for an ability to interfere with mutant huntingtin protein propagation, which has been linked to disease progression. The hope, of course, is that drugs that interfere with seeding of huntingtin in the laboratory will show clinical efficacy in patients.

Z. Tan et al., Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin. Mol. Psychiatry 10.1038/mp.2015.81 (2015). [Full Text]

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