Downregulation of Pten Improves Huntington's Disease Phenotype by Reducing Htt Aggregates and Cell Death.

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Tác giả: Sanchi Ahuja, Bhavya Gohil, Aninda Sundar Modak, Chandramouli Mukherjee, Nisha, Bhavani Shankar Sahu, Mayanglambam Dhruba Singh, N Tarundas Singh, Deepti Thapliyal

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : Molecular neurobiology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 717892

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that stems from the expansion of CAG repeats within the coding region of Huntingtin (HTT) gene. Currently, there exists no effective therapeutic intervention that can prevent the progression of the disease. Our study aims to identify a novel genetic modifier with therapeutic potential. We employ transgenic flies containing HTT.ex1.Q93 and mRFP-HTT.588.Q138 constructs, which encode mutant pathogenic Huntingtin (Htt) proteins featuring 93 and 138 polyglutamine (Q) repeats respectively. The resultant mutant proteins cause 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 the 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 found the reduction in both Htt aggregate and caspase levels which are involved in the apoptotic pathway. In alignment with the genetic modulation of Pten, we elucidated the protective role of Pten inhibition through the utilization of VO-OHpic. VO-OHpic improved the climbing ability of flies and reduced the poly(Q) aggregates and apoptosis levels. A similar reduction in Htt 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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