PXD041784-1

PXD041784 is an original dataset announced via ProteomeXchange.

Title	HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent
Description	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.
HostingRepository	jPOST
AnnounceDate	2024-02-20
AnnouncementXML	Submission_2024-02-20_11:05:13.383.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD041784
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Hector Palacios
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; N6-acetyl-L-lysine
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-24 11:07:21	ID requested
⏵ 1	2024-02-20 11:05:13	announced

Dataset with its publication pending

submitter keyword: LC-MSMS, HtrA1, serine protease, dementia

Meredith E. Jackrel
lab head
Hector Palacios
contact affiliation	WUSTL
dataset submitter

jPOST dataset URI

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