HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.

Autor: Chen S; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Puri A; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Bell B; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Fritsche J; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Palacios HH; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Balch M; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Sprunger ML; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Howard MK; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Ryan JJ; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA., Haines JN; Department of Neurology, Washington University, St. Louis, MO, 63130, USA., Patti GJ; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA.; Department of Medicine, Washington University, St. Louis, MO, 63130, USA., Davis AA; Department of Neurology, Washington University, St. Louis, MO, 63130, USA., Jackrel ME; Department of Chemistry, Washington University, St. Louis, MO, 63130, USA. mjackrel@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 18; Vol. 15 (1), pp. 2436. Date of Electronic Publication: 2024 Mar 18.
DOI: 10.1038/s41467-024-46538-8
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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