Directly Reprogrammed Huntington's Disease Neural Precursor Cells Generate Striatal Neurons Exhibiting Aggregates and Impaired Neuronal Maturation

Directly reprogrammed Huntington's disease induced neural precursor cells generate DARPP32+ striatal neurons exhibiting ubiquitinated huntingtin aggregates, altered neuronal morphologies, reduced hyperpolarisation, and reduced BDNF expression that correlates with age of symptom onset and increased CAG expansion. AbstractHuntington'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 2021Significance StatementThis man...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Translational and Clinical Research Source Type: research