<<< Full experiment listing

PXD044806-1

PXD044806 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleHTRA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent
DescriptionParkinson 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.
HostingRepositoryjPOST
AnnounceDate2024-02-20
AnnouncementXMLSubmission_2024-02-20_11:04:35.287.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD044806
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterHector Palacios
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListS-carboxamidomethyl-L-cysteine; L-methionine sulfoxide; alpha-amino acetylated residue; 2-pyrrolidone-5-carboxylic acid (Gln); deamidated L-glutamine; deamidated L-asparagine
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-08-23 11:25:50ID requested
12024-02-20 11:04:35announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: LC-MSMS, HtrA1, serine protease, dementia
Contact List
Meredith E. Jackrel
lab head
Hector Palacios
contact affiliationWUSTL
dataset submitter
Full Dataset Link List
jPOST dataset URI
Dataset FTP location
NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.jpostdb.org/JPST002295/