Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Biophys J. 2019 Apr 23;116(8):1380-1385. doi: 10.1016/j.bpj.2019.03.007. Epub 2019 Mar 22.
Protein misfolding and overloaded proteostasis networks underlie a range of neurodegenerative diseases. No cures exist for these diseases, but developing effective therapeutic agents targeting the toxic, misfolded protein species in disease is one promising strategy. AAA+ (ATPases associated with diverse cellular activities) protein translocases, which naturally unfold and translocate substrate proteins, could be potent therapeutic agents to disassemble toxic protein conformers in neurodegenerative disease. Here, we discuss repurposing AAA+ protein translocases Hsp104 and proteasome-activating nucleotidase (PAN) to alleviate the toxicity from protein misfolding in neurodegenerative disease. Hsp104 effectively protects various animal models from neurodegeneration underpinned by protein misfolding, and enhanced Hsp104 variants strongly counter neurodegenerative disease-associated protein misfolding toxicity in yeast, Caenorhabditis elegans, and mammalian cells. Similarly, a recently engineered PAN variant (PAN) mitigates photoreceptor degeneration instigated by protein misfolding in a mouse model of retinopathy. Further study and engineering of AAA+ translocases like Hsp104 and PAN will reveal promising agents to combat protein misfolding toxicity in neurodegenerative disease.
蛋白质错误折叠和过载的蛋白质稳态网络是多种神经退行性疾病的基础。这些疾病目前尚无治愈方法，但开发针对疾病中有毒、错误折叠的蛋白质的有效治疗药物是一种很有前途的策略。AAA+（与多种细胞活动相关的 ATP 酶）蛋白易位酶可以自然展开和转运底物蛋白，可能是一种有效的治疗药物，可以在神经退行性疾病中分解有毒的蛋白质构象。在这里，我们讨论了重新利用 Hsp104 和蛋白酶体激活核苷酸酶 (PAN) 等 AAA+蛋白易位酶来减轻神经退行性疾病中蛋白质错误折叠的毒性。Hsp104 有效地保护了各种动物模型免受由蛋白质错误折叠引起的神经退行性变，并且增强的 Hsp104 变体在酵母、秀丽隐杆线虫和哺乳动物细胞中强烈对抗与神经退行性疾病相关的蛋白质错误折叠毒性。同样，最近设计的 PAN 变体（PAN）减轻了由视网膜病变小鼠模型中的蛋白质错误折叠引发的光感受器变性。对 Hsp104 和 PAN 等 AAA+易位酶的进一步研究和工程化将揭示出有希望的对抗神经退行性疾病中蛋白质错误折叠毒性的药物。
