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

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Listed:
  • 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
    Washington University)

  • Albert A. Davis

    (Washington University)

  • Meredith E. Jackrel

    (Washington University)

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.

Suggested Citation

  • 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, 2024. "HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46538-8
    DOI: 10.1038/s41467-024-46538-8
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    1. Liangqian Huang & Trisha Agrawal & Guixin Zhu & Sixiang Yu & Liming Tao & JiaBei Lin & Ronen Marmorstein & James Shorter & Xiaolu Yang, 2021. "DAXX represents a new type of protein-folding enabler," Nature, Nature, vol. 597(7874), pages 132-137, September.
    2. Jeff Sevigny & Ping Chiao & Thierry Bussière & Paul H. Weinreb & Leslie Williams & Marcel Maier & Robert Dunstan & Stephen Salloway & Tianle Chen & Yan Ling & John O’Gorman & Fang Qian & Mahin Arastu , 2016. "The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease," Nature, Nature, vol. 537(7618), pages 50-56, September.
    3. J. Paul Taylor & Robert H. Brown & Don W. Cleveland, 2016. "Decoding ALS: from genes to mechanism," Nature, Nature, vol. 539(7628), pages 197-206, November.
    4. Nadinath B. Nillegoda & Janine Kirstein & Anna Szlachcic & Mykhaylo Berynskyy & Antonia Stank & Florian Stengel & Kristin Arnsburg & Xuechao Gao & Annika Scior & Ruedi Aebersold & D. Lys Guilbride & R, 2015. "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation," Nature, Nature, vol. 524(7564), pages 247-251, August.
    5. Sara Reardon, 2023. "FDA approves Alzheimer’s drug lecanemab amid safety concerns," Nature, Nature, vol. 613(7943), pages 227-228, January.
    6. Christopher M. Dobson, 2003. "Protein folding and misfolding," Nature, Nature, vol. 426(6968), pages 884-890, December.
    Full references (including those not matched with items on IDEAS)

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