Investigating calcineurin regulation of pathological TDP-43 phosphorylation in ALS

肌萎缩侧索硬化症是一种严重的进行性神经退行性疾病。 以大脑和脊髓中运动神经元的退化为特征，导致神经源性肌肉 消瘦、瘫痪和死亡。近95%的肌萎缩侧索硬化症患者的病理特征是磷酸化 TDP-43蛋白在神经元和神经胶质细胞中的包涵体。此外，编码人类基因组的基因突变 TDP-43已被证明可导致一些ALS病例，表明正常的TDP-43对神经元至关重要 健康。TDP-43的磷酸化降低其周转率，增加其聚集性，并促进 神经毒性和神经退行性变。最近的研究发现，磷酸酶钙调神经磷酸酶是一个关键 磷酸化TDP-43(PTDP)积累的调节因子。通过使pTDP去磷酸化，钙调神经磷酸酶 降低神经毒性pTDP水平，保护包括神经变性在内的疾病表型。 对肌萎缩侧索硬化症的TDP-43病理控制机制的理解对于设计 神经保护策略。 这个提案描述了探索细胞和分子变化的实验，这些变化促进了 TDP-43靶向钙调神经磷酸酶活性，重点开发治疗 肌萎缩侧索硬化症的治疗干预。这项工作将1)阐明钙调神经磷酸酶的控制机制 激活和pTDP清除，2)评价钙调神经磷酸酶的激活作为一种新的治疗策略 清除pTDP，3)，提供神经毒性应激后细胞恢复的新信息，以及4) 可能为治疗干预提供额外的靶点。这项工作的完成将提前 了解ALS潜在的疾病过程，并提供新的临床前验证 治疗方法。

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease characterized by degeneration of motor neurons in the brain and spinal cord, resulting in neurogenic muscle wasting, paralysis, and death. Nearly 95% of ALS cases have pathology featuring phosphorylated inclusions of the TDP-43 protein in neurons and glial cells. Furthermore, mutations in the gene coding for TDP-43 have been shown to cause some cases of ALS, indicating normal TDP-43 is critical for neuronal health. Phosphorylation of TDP-43 reduces its turnover, increases its aggregation, and promotes neurotoxicity and neurodegeneration. Recent work has identified the phosphatase calcineurin as a key regulator of phosphorylated TDP-43 (pTDP) accumulation. By dephosphorylating pTDP, calcineurin reduces levels of neurotoxic pTDP and protects against disease phenotypes, including neurodegeneration. An understanding of the mechanisms controlling TDP-43 pathology in ALS is critical to the design of neuroprotective strategies. This proposal describes experiments exploring the cellular and molecular changes that promote TDP-43-targeted calcineurin phosphatase activity, with a focus on the development of therapeutic interventions for the treatment of ALS. This work will 1) elucidate mechanisms controlling calcineurin activation and pTDP clearance, 2) evaluate activation of calcineurin as a novel therapeutic strategy for the clearance of pTDP, 3), provide new information about cellular recovery following neurotoxic stress, and 4) may provide additional targets for therapeutic intervention. Completion of this work will advance understanding of the disease processes underlying ALS and provide preclinical validation of a new therapeutic approach.