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bioRxiv · 10.1101/2024.03.28.587147

Protective role of Pten downregulation in Huntington's Disease models

Nisha,·Thapliyal, D.·Gohil, B.·Modak, A. S.·Ahuja, S.·Singh, N. T.·Sahu, B. S.·Singh, M. D.
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Abstract

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder that stems from the expansion of CAG repeats within the coding region of the Huntingtin gene. Currently, there exists no effective therapeutic intervention that can prevent the progression of the disease. Our investigation aims to identify a novel genetic modifier with therapeutic potential. We employ transgenic flies containing Htt93Q and Htt138Q.mRFP constructs, which encode mutant pathogenic Huntingtin proteins featuring 93 and 138 polyglutamine (Q) repeats, respectively. The resultant mutant protein causes the loss of photoreceptor neurons in the eye and a progressive loss of neuronal tissues in the brain and motor neurons in Drosophila. Several findings have demonstrated the association of HD with growth factor signaling defects. Phosphatase and tensin homolog (Pten) have been implicated in the negative regulation of insulin signaling/receptor tyrosine signaling pathway which regulates the growth and survival of cells. In the present study, we downregulated Pten and found a significant improvement in morphological phenotypes in the eye, brain, and motor neurons. These findings were further correlated with the enhancement of the functional vision and climbing ability of the flies. We also noted the reduction in both poly(Q) aggregate levels and caspase activity which are involved in the apoptotic pathway. Moreover, we elucidated the protective role of Pten inhibition through the utilization of VO-OHpic (referred to as PTENi). In alignment with the genetic modulation of Pten, pharmaceutical inhibition of Pten improved the climbing ability of flies and reduced the poly(Q) aggregates and apoptosis levels. A similar reduction in poly(Q) aggregates was observed in the mouse neuronal inducible HD cell line model. Our study illustrates that Pten inhibition is a potential therapeutic approach for HD.

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Nisha,, Thapliyal, D., Gohil, B., Modak, A. S., Ahuja, S., Singh, N. T., Sahu, B. S., Singh, M. D.. 2024-04-01. Protective role of Pten downregulation in Huntington's Disease models. https://doi.org/10.1101/2024.03.28.587147

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