Neurology Central

Promising new weapon in the war against Huntington’s disease

Using an experimental approach to modeling neuronal circuitry, researchers from the University of California San Diego (CA, USA) led by William Mobley, have identified a protein subunit that rescues molecular defects occurring in Huntington’s disease (HD).
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HD pathogenesis is caused by an expanded CAG repeat in the huntingtin gene, resulting in mutant huntingin (mHTT) protein which is thought to have an adverse impact on numerous cellular functions. It is believed mHTT contributes to corticostriatal atrophy and reductions in brain-derived neurotrophic factor (BDNF).

In this study, the HD corticostriatal circuit was recreated in microfluidic chamber co-cultures by connecting cortical and striatal neurons from HD and wild-type mouse models. This novel co-culture method demonstrated several features of HD pathology including reduced synaptic connectivity, striatal neuron atrophy and deficient BDNF axonal transport.

“Our experimental design provides an invaluable system for studying important cellular and molecular events underlying HD,” commented first author Xiaobei Zhao (University of California San Diego). “The new model and the ability to recreate the abnormal circuit is more physiologically relevant than many other models. Most important, it facilitates study of disease mechanisms and possible new disease-modifying treatments.”

T-complex 1 ring complex (TRiC) is a cytosolic chaperonin involved in protein folding and degradation of misfolded proteins. The team demonstrated that overexpression of TRiC subunits in the model cortical neurons significantly reduced mHTT levels, restored BDNF axonal transport and prevented striatal neuron atrophy.

This study has therefore highlighted TRiC as a promising approach for reducing mHTT levels with the aim of reversing HD pathogenesis. “The next step is to test this in vivo. If the phenotype of the HD mouse model can be rescued, it’s possible that TRiC could be used to treat Huntington’s disease” concluded Zhao.

Sources: Zhao X, Chen XQ, Han E et al. TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease. PNAS. doi: 10.1073/pnas.1603020113 (2016) (Epub ahead of print);