Department of Chemistry, Washington University, St. Louis, MO, 63130, USA.
Department of Neurology, Washington University, St. Louis, MO, 63130, USA.
Nat Commun. 2024 Mar 18;15(1):2436. doi: 10.1038/s41467-024-46538-8.
Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders.
帕金森病（PD）与α-突触核蛋白（α-syn）在路易体中的错误折叠和积累密切相关。PDZ 丝氨酸蛋白酶 HTRA1 降解与阿尔茨海默病相关的纤维状 tau，而线粒体 HTRA2 的失活突变与 PD 有关。在这里，我们报告 HTRA1 抑制 α-syn 以及 FUS 和 TDP-43 的聚集，这些蛋白与肌萎缩侧索硬化症（ALS）和额颞叶痴呆有关。HTRA1 的蛋白酶结构域对于抑制聚集是必需且充分的，但这种活性与蛋白水解无关。此外，HTRA1 解聚预先形成的 α-syn 纤维，使其无法引发内源性 α-syn 的聚集，而降低 HTRA1 的表达则促进 α-syn 的聚集。HTRA1 通过靶向 NAC 结构域来重塑 α-syn 纤维，NAC 结构域是催化 α-syn 淀粉样形成的关键结构域。最后，HTRA1 可使 α-syn 纤维解毒，并防止其在原代神经元中形成过度磷酸化的 α-syn 聚集物。我们的研究结果表明，HTRA1 可能是一系列神经退行性疾病的治疗靶点。
