Department of Ophthalmology, West Virginia University, Morgantown, West Virginia, United States of America.
Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States of America.
PLoS One. 2024 Oct 3;19(10):e0308058. doi: 10.1371/journal.pone.0308058. eCollection 2024.
Neurodegenerative diseases are characterized by the presence of misfolded and aggregated proteins which are thought to contribute to the development of the disease. In one form of inherited blinding disease, retinitis pigmentosa, a P23H mutation in the light-sensing receptor, rhodopsin causes rhodopsin misfolding resulting in complete vision loss. We investigated whether a xenogeneic protein-unfolding ATPase (unfoldase) from thermophilic Archaea, termed PANet, could counteract the proteotoxicity of P23H rhodopsin. We found that PANet increased the number of surviving photoreceptors in P23H rhodopsin mice and recognized rhodopsin as a substate in vitro. This data supports the feasibility and efficacy of using a xenogeneic unfoldase as a therapeutic approach in mouse models of human neurodegenerative diseases. We also showed that an archaeal proteasome, called the T20S can degrade rhodopsin in vitro and demonstrated that it is feasible and safe to express gateless T20S proteasomes in vivo in mouse rod photoreceptors. Expression of archaeal proteasomes may be an effective therapeutic approach to stimulate protein degradation in retinopathies and neurodegenerative diseases with protein-misfolding etiology.
神经退行性疾病的特征是存在错误折叠和聚集的蛋白质，这些蛋白质被认为是导致疾病发展的原因。在一种遗传性致盲疾病——色素性视网膜炎中，光感受器视紫红质中的 P23H 突变导致视紫红质错误折叠，从而导致完全失明。我们研究了一种来自嗜热古菌的异种蛋白展开 ATP 酶（展开酶），即 PANet，是否可以抵消 P23H 视紫红质的蛋白毒性。我们发现，PANet 增加了 P23H 视紫红质小鼠中存活的光感受器数量，并在体外识别视紫红质为亚基。这些数据支持使用异种展开酶作为人类神经退行性疾病小鼠模型的治疗方法的可行性和有效性。我们还表明，一种称为 T20S 的古菌蛋白酶体可以在体外降解视紫红质，并证明在体内表达无门 T20S 蛋白酶体在小鼠杆状光感受器中是可行且安全的。古菌蛋白酶体的表达可能是一种有效的治疗方法，可刺激具有蛋白错误折叠病因的视网膜病变和神经退行性疾病中的蛋白降解。
