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

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...
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Autor*in:	Sheng Chen [verfasserIn] Anuradhika Puri [verfasserIn] Braxton Bell [verfasserIn] Joseph Fritsche [verfasserIn] Hector H. Palacios [verfasserIn] Maurie Balch [verfasserIn] Macy L. Sprunger [verfasserIn] Matthew K. Howard [verfasserIn] Jeremy J. Ryan [verfasserIn] Jessica N. Haines [verfasserIn] Gary J. Patti [verfasserIn] Albert A. Davis [verfasserIn] Meredith E. Jackrel [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Übergeordnetes Werk:	In: Nature Communications - Nature Portfolio, 2016, 15(2024), 1, Seite 18
Übergeordnetes Werk:	volume:15 ; year:2024 ; number:1 ; pages:18

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41467-024-46538-8

Katalog-ID:	DOAJ095734643

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allfieldsSound	10.1038/s41467-024-46538-8 doi (DE-627)DOAJ095734643 (DE-599)DOAJd3a814cfc6b44384be88ec4319bf5430 DE-627 ger DE-627 rakwb eng Sheng Chen verfasserin aut HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Science Q Anuradhika Puri verfasserin aut Braxton Bell verfasserin aut Joseph Fritsche verfasserin aut Hector H. Palacios verfasserin aut Maurie Balch verfasserin aut Macy L. Sprunger verfasserin aut Matthew K. Howard verfasserin aut Jeremy J. Ryan verfasserin aut Jessica N. Haines verfasserin aut Gary J. Patti verfasserin aut Albert A. Davis verfasserin aut Meredith E. Jackrel verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46538-8 kostenfrei https://doaj.org/article/d3a814cfc6b44384be88ec4319bf5430 kostenfrei https://doi.org/10.1038/s41467-024-46538-8 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
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author	Sheng Chen
spellingShingle	Sheng Chen misc Science misc Q HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
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topic_title	HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
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title	HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
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author_browse	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 Meredith E. Jackrel
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title_sort	htra1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
title_auth	HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
url	https://doi.org/10.1038/s41467-024-46538-8 https://doaj.org/article/d3a814cfc6b44384be88ec4319bf5430 https://doaj.org/toc/2041-1723
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HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species

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