HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.
HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.
复制标题
HTRA1 分解 α-突触核蛋白淀粉样原纤维，并将其转化为无毒和播种无能的物种。
DOI：
10.1038/s41467-024-46538-8
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发表时间：
2024
影响因子：
16.6
通讯作者：
Jackrel,MeredithE
中科院分区：
文献类型：
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作者：
Chen,Sheng;Puri,Anuradhika;Bell,Braxton;Fritsche,Joseph;Palacios,HectorH;Balch,Maurie;Sprunger,MacyL;Howard,MatthewK;Ryan,JeremyJ;Haines,JessicaN;Patti,GaryJ;Davis,AlbertA;Jackrel,MeredithE
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聚密切相关。PDZ丝氨酸蛋白酶HTRA 1降解与阿尔茨海默病相关的纤维状tau，并且线粒体HTRA 2的失活突变与PD有关。在这里，我们报告HTRA 1抑制α-syn以及FUS和TDP-43的聚集，这与肌萎缩侧索硬化症（ALS）和额颞叶痴呆有关。HTRA 1的蛋白酶结构域对于抑制聚集是必要的和足够的，然而这种活性是蛋白水解独立的。此外，HTRA 1使预先形成的α-syn原纤维解聚，使得它们不能接种内源性α-syn的聚集，而减少HTRA 1表达促进α-syn接种。HTRA 1通过靶向NAC结构域（催化α-syn淀粉样蛋白生成的关键结构域）重塑α-syn纤维。最后，HTRA 1使α-syn纤维解毒，并防止在原代神经元中形成过度磷酸化的α-syn积累。我们的研究结果表明，HTRA 1可能是一系列神经退行性疾病的治疗靶点。
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.