GSK3磷酸化DNAJB6b造成阿茲海默症及亨廷頓舞蹈症中不正常蛋白質聚集

Abstract

統計已知大於九成的神經退化疾病是找不到遺傳相關變異的，這意味著大部分的病人是在環境中的受到壓力累積而在老年時期產生疾病，我們實驗室日前在酵母菌模型中發現與HSP90的共伴侶蛋白Ids2在卡路里限制的壓力下會增加其磷酸化，並喪失功能、細胞存活率顯著降低。 反觀人類中，已知伴侶蛋白HSP70參與最多重要機制，而參與其中的重要輔助型伴侶蛋白HSP40所參與的機制尚未被完全了解，實驗室在幾年前針對一系列DNAJ family蛋白和疾病蛋白進行screening，想找出與清除致病蛋白相關的輔助型伴侶蛋白，學長發現其中DNABJ6家族與阿茲海默症的致病蛋白不正常堆積有關，且先前研究也表明亨廷頓舞蹈症中的huntingtin 蛋白也與其相關。有鑑於DNAJB6b在這兩種疾病的貢獻，我想去釐清是否上頭有磷酸化能調控其活性，並想探討上游的主要激酶、壓力來源為何。 在這裡，我發現了對於DNAJB6b有重要調控作用的磷酸化位點Ser 15，並發現Ser 15受GSK3調控，我推測GSK3活化時將使Ser 15位點磷酸化增加，進而降低DNAJB6b與受質結合的能力導造成胞致病蛋白不正常堆積，本篇的發現可以了解神經退化性疾病的機轉，為治療及診斷方法提供新方向。

Statistics show that over 90% of neurodegenerative diseases cannot be attributed to genetic variations (Blass, 2010), this suggests that most patients develop the diseases in their later years due to accumulated stress from environmental factors. Recently, our laboratory discovered a co-chaperone protein of HSP90 in a yeast model, Ids2, which undergoes phosphorylation to lose its normal function, leading to a significant decrease in cell viability under calorie restriction. In humans, HSP70 is the main chaperone protein in the chaperone system, which isassisted by co-chaperone protein HSP40. Several years ago, our lab conducted a screening and identified that the human DNABJ6 family is associated with an abnormal accumulation of pathogenic tau proteins in Alzheimer's disease (Appendix 2.). Moreover, a previous study also indicated its relevance to Huntington’s disease (Gillis et al., 2013; Thiruvalluvan et al., 2020). Considering the contribution of DNAJB6b to these two diseases, I aim to investigate whether its activity can be regulated by phosphorylation and explore the main upstream kinases and related stress. Here, I found Ser 15 phosphorylation plays an important role in DNAJB6b activity and is specifically regulated by GSK3. I speculate that activation of GSK3 increases the phosphorylation of Ser15, thereby reducing the binding capacity of DNAJB6b to its substrate, which leads to abnormal accumulation of pathogenic proteins in cells. These findings shed light on the mechanism of neurodegenerative diseases and provide new directions for treatment and diagnostic approaches. My findings also dissect the disease mechanisms and provide new directions for diagnosis and treatment.