During this period, the project team has further characterized the previously developed lead molecules of interest, and shown that inhibition of PIP4K by a small molecule inhibitor or silencing leads to change in the equilibrium of phosphatidyl ionosotides that increases autophagy and reduce mutant huntingtin protein in human patient fibroblasts and aggregates in neurons. In a Huntington Drosophila model silencing the gene for PIP4K leads to a recovery of motor performance and retinal degeneration, caused by the mutant huntingtin protein. This suggests that PIP4K is a novel pharmacological target for neurodegenerative diseases such as Huntington disease.
| Al-Ramahi, Ismael; Giridharan, Sai Srinivas Panapakkam; Chen, Yu-Chi et al. (2017) Inhibition of PIP4K? ameliorates the pathological effects of mutant huntingtin protein. Elife 6: |
