Proteomics

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HTRA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent


ABSTRACT: Parkinson disease (PD) is closely linked to the misfolding and accumulation of α-synuclein (α-syn) into Lewy bodies. HTRA1 is a PDZ serine protease that degrades fibrillar tau, which is associated with Alzheimer disease (AD). Further, inactivating mutations to mitochondrial HTRA2 have been implicated in PD. Here, we establish that HTRA1 inhibits the aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We demonstrate that the protease domain of HTRA1 is necessary and sufficient for inhibition of aggregation, yet this activity is independent of HTRA1 proteolytic activity. Further, we find that HTRA1 also disaggregates preformed α-syn fibrils, which may promote their clearance. Treatment of α-syn fibrils with HTRA1 renders α-syn incapable of seeding the aggregation of endogenous α-syn in mammalian biosensor cells. We find that HTRA1 remodels α-syn by specifically targeting the NAC domain, which is the key domain that catalyzes α-syn oligomerization and fibrillization. Finally, in a primary neuron model of α-syn aggregation, we show that HTRA1 and its proteolytically inactive form both detoxify α-syn and prevent the formation of hyperphosphorylated α-syn accumulations. Our findings suggest that HTRA1 prevents aggregation and promotes disaggregation of multiple disease-associated proteins, and may be a therapeutic target for treating a range of neurodegenerative disorders.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Meredith E. Jackrel 

PROVIDER: PXD044806 | JPOST Repository | Tue Feb 20 00:00:00 GMT 2024

REPOSITORIES: jPOST

Dataset's files

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Action DRS
MSB-9491%2052915%20WUSTL%20Chen%20091423.sf3 Other
MSB-9491%20WUSTL%20Chen%20061821.sf3 Other
MSB52915A%20(F177392).mzid Mzid
MSB52915A%20(F177392).mzid_MSB52915A_(F177392).MGF Mzid
MSB52915A.raw Raw
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