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

Stem Cells. 2021 Oct;39(10):1410-1422. doi: 10.1002/stem.3420. Epub 2021 May 27.


Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized 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 depolarized 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.

Keywords: Huntington's disease; differentiation; direct reprogramming; disease modeling; lineage conversion; striatal neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Corpus Striatum
  • Humans
  • Huntington Disease* / metabolism
  • Neural Stem Cells* / metabolism
  • Neurogenesis
  • Neurons / metabolism