To accelerate their discovery of new treatments for Huntington’s disease (HD), researchers at the University College of London developed a human neuronal cell model of the disease for use in high-throughput screening of potential therapies.
Existing HD cellular models, which are mostly non-human and non-neuronal, fail to recapitulate the disease’s biochemical milieu. Dr. Sarah Tabrizi and team at the University College of London created a model that replicates HD pathogenesis in her quest to develop cell-based treatments for individuals at the earliest stages of the disease.
In HD, a CAG mutation leads to repeat expansion in exon 1, which codes for the toxic huntingtin protein (HTT), leading to an elongated poly-glutamine (polyQ) stretch in the N-terminal domain. The lengths of CAG repeats are associated with disease onset and severity, with longer repeat lengths increasing the risk for an earlier onset and faster progression. Inheriting more than 55 CAG repeats can also lead to juvenile-onset of the debilitating disease.
The lab engineered human neural stem cells (NSC) to express exon 1 HTT fragments with varying polyQ-length expansions. With either 30, 71, or 122 CAG repeats, the NSC lines efficiently differentiated into neurons expressing exon 1 HTT, including mutant HTT-positive inclusion bodies and mitochondrial dysfunctions related to CAG length.
These new models may serve as a critical resource for researchers by providing an in vitro model for high-throughput screening of novel therapies for HD.
For research use only. Not for use in diagnostic procedures.
