Cell models of Huntington's disease have been very important for understanding the cell biology of the disorder and for testing potential therapeutics The recent development of human induced pluripotent stem cell (iPSC) models has greatly enhanced our ability to model disease in human cells. As part of the NINDS funded HD iPSC Consortium, we have developed a cell model of HD. However, as valuable as this model is, the differentiation to medium spiny neurons is very long, cumbersome and expensive, making study of the cells and screening for therapeutics very difficult. We therefore now propose to generate immortalized striatal precursors from the HD iPS cells.
In Specific Aim 1, we will use HD and control iPS cells differentiated to striatal precursors for immortalization with viral vectors, and optimize protocols for differentiation to neurons with a mature striatal medium spiny neuron phenotype.
In Specific Aim 2, we will assess the cells for CAG- repeat-expansion-dependent toxicity and rescue, and format the model as a screenable assay. These studies taken together will permit the development of a novel cell model of HD which will have features similar to the iPS cell model, but be more reproducible and tractable. These cells should be very valuable for studying HD pathogenesis and for screening for novel neuroprotective therapeutics.
Cell models of Huntington's disease have been very important for understanding the cell biology of the disorder and for testing potential therapeutics. We now propose to generate immortalized striatal precursors from HD iPS cells as a new cell model of HD. These cells should be very valuable for studying HD pathogenesis and for screening for novel neuroprotective therapeutics.
|Gomez-Pastor, Rocio; Burchfiel, Eileen T; Neef, Daniel W et al. (2017) Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nat Commun 8:14405|
|Ratovitski, Tamara; Chaerkady, Raghothama; Kammers, Kai et al. (2016) Quantitative Proteomic Analysis Reveals Similarities between Huntington's Disease (HD) and Huntington's Disease-Like 2 (HDL2) Human Brains. J Proteome Res 15:3266-83|
|Ross, Christopher A; Akimov, Sergey S (2014) Human-induced pluripotent stem cells: potential for neurodegenerative diseases. Hum Mol Genet 23:R17-26|