The Use of HDAC4-MAP1S System in the Treatment of Huntington’s Disease
Introduction. Huntington’s Disease (HD) is a trinucleotide repeat disorder which results in a neurodegenerative disease caused by the accumulation of mutant huntingtin protein (mHTT). The disease is the most common trinucleotide repeat disorder in the world, and it is fatal1. Mutant Huntingtin Protein and Autophagy. Cellular models grown with mHTT have shown neurodegeneration. Decreasing the translation of the mHTT decreased neurodegeneration and neurotoxicity. This cellular model established a link between mHTT aggregation and neurodegeneration, as well as provided a potential therapeutic avenue2. Another study noted the autophagy levels in cells affected by mHTT accumulation were low. A cellular model affected by mHTT were injected with Euporium Hydroxide Nanorods to induce autophagy in the cells. After measuring the increased autophagy levels in the cells affected by mHTT, it was found that inducing autophagy reduced mHTT aggregation. This increased cell viability and lifespan due to increased autophagy. This is a potential therapeutic method to decrease mHTT aggregation3. MAP1S and its Effect on Autophagy in Cells. Studies on mouse models with dysfunctional MAP1S were shown to have a decreased autophagy. In wild type cells, MAP1S gene facilitated autophagy of fibronectin. This decrease in autophagy due to MAP1S deletion caused a decrease in the lifetime of these mice due abnormal protein accumulation. MAP1S is one of the ways autophagy can be induced in a cell, decreasing aberrant protein accumulation and cell toxicity, while increasing lifespan. With MAP1S established as a key part in autophagy in cells, it becomes important in our search for therapeutic interventions in HD.4 HD: HDAC4 decreasing MAP1S activity in neurons. A study showed the presence of HDAC4 protein in the cytoplasmic aggregations of mHTT. HDAC4 overexpression was found to cause HDAC4-MAP1S interactions in the cytoplasm, resulting in altered MAP1S activity and therefore decreasing autophagy. HDAC4 decreased the stability of MAP1S and decreased the level of acetylated MAP1S, which is important for MAP1S’s autophagy function. HDAC4 specific siRNAs were then introduced to downregulate the expression of HDAC4, which increased autophagy5. A study testing HDAC4 inhibitor in mice expressing mHTT showed an increase in autophagy and a decrease in HD symptoms6. Using an HDAC4 Inhibitor has been shown in mouse models to decrease the negative effects of HDAC4 in HD, and can increase the lifespan and health of the mice. This model provides a potential therapy for the most prevalent fatal Trinucleotide Repeat disease in the world.
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