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

Sheng Chen, Anuradhika Puri, Braxton Bell, Joseph Fritsche, Hector H. Palacios, Maurie Balch, Macy L. Sprunger, Matthew K. Howard, Jeremy J. Ryan, Jessica N. Haines, Gary J. Patti, Albert A. Davis and Meredith E. Jackrel ()
Additional contact information
Sheng Chen: Washington University
Anuradhika Puri: Washington University
Braxton Bell: Washington University
Joseph Fritsche: Washington University
Hector H. Palacios: Washington University
Maurie Balch: Washington University
Macy L. Sprunger: Washington University
Matthew K. Howard: Washington University
Jeremy J. Ryan: Washington University
Jessica N. Haines: Washington University
Gary J. Patti: Washington University
Albert A. Davis: Washington University
Meredith E. Jackrel: Washington University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46538-8

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