Directly reprogrammed Huntington's disease neural precursor cells generate striatal neurons exhibiting aggregates and impaired neuronal maturation.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by the progressive loss of striatal medium spiny neurons. Using a highly efficient protocol for direct reprogramming of adult human fibroblasts with chemically modified mRNA, we report the first generation of HD induced neural precursor cells (iNPs) expressing striatal lineage markers that differentiated into DARPP32+ neurons from individuals with adult-onset HD (41-57 CAG). While no transcriptional differences between normal and HD reprogrammed neurons were detected by NanoString nCounter analysis, a subpopulation of HD reprogrammed neurons contained ubiquitinated polyglutamine aggregates. Importantly, reprogrammed HD neurons exhibited impaired neuronal maturation, displaying altered neurite morphology and more depolarised resting membrane potentials. Reduced BDNF protein expression in reprogrammed HD neurons correlated with increased CAG repeat lengths and earlier symptom onset. This model represents a platform for investigating impaired neuronal maturation and screening for neuronal maturation modifiers to treat HD. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: This manuscript represents the first reported generation of directly reprogrammed Huntington's disease neural precursor cells and DARPP32+ neurons from adult-onset Huntington's disease patients. We observed the formation of ubiquitinated polyglutamine aggregates and impaired neuronal maturation in reprogrammed Huntington's disease neurons as well as a correlation between BDNF protein expression and Huntington's disease severity. This work represents a novel platform to screen for new targets for the treatment of Huntington's disease.