Poster Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

The use of direct cell reprogramming to identify novel targets to treat Huntington’s disease. (#107)

Amy Chapman 1 , Lieke Burgers 1 , Bronwen Connor 1
  1. University of Auckland, AUCKLAND, New Zealand

Huntington’s disease (HD) is an autosomal dominant genetic neurodegenerative disease for which there is no treatment. We have developed a unique chemically modified mRNA-based protocol to directly reprogram adult human dermal fibroblasts (aHDFs) into induced neural precursor cells and differentiate them into different neuronal subtypes. Using this technology, small molecules were combined with overexpression of the pro-neural factors SOX2 and PAX6 to generate human induced lateral ganglionic eminence precursors from normal and HD patient-derived aHDFs. Subsequent differentiation gave rise to high yields of DARPP32+ medium spiny neurons (MSNs). BDNF mRNA and protein expression was reduced in HD patient-derived MSNs, while expression of the BDNF receptor TRKB was maintained. This indicates impaired transcriptional regulation of BDNF in human HD MSNs. Repression element silencing factor-1 (REST) associates with the Huntingtin gene (Htt). In the presence of mutant Htt, REST undergoes translocation to the nucleus, repressing BDNF. Using our HD human cell model, we investigated whether lithium can be re-directed for the treatment of HD by activating Wnt and P120-catenin signalling preventing REST repression of BDNF. Autophagy is altered in HD. Using natural compounds, we targeted autophogosomes and lysosomes in our HD human cell model to better understand their dysfunction in HD.

  • Have you presented your abstract at another international meeting?: No