PXD025561

PXD025561 is an original dataset announced via ProteomeXchange.

Title	Slowing prion disease via M1 muscarinic receptors is associated with reduced neuroinflammation and down-regulation of neurodegenerative disease markers
Description	Currently there are no treatments that can slow or halt the progression of dementia’s including Alzheimer’s disease. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which shows many of the pathological hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulated as well as a normalisation in the expression of markers associated neurodegeneration and Alzheimer’s disease. Furthermore, synaptic proteins and post-synaptic signalling components disrupted in disease are maintained by VU846. We conclude that allosteric regulation of M1-receptors have the potential to reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:44:13.843.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD025561
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Andrew Bottrill
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-22 06:42:35	ID requested
1	2023-03-14 10:55:55	announced
⏵ 2	2023-11-14 08:44:14	announced	2023-11-14: Updated project metadata.

10.6019/PXD025561;

Dwomoh L, Rossi M, Scarpa M, Khajehali E, Molloy C, Herzyk P, Mistry SN, Bottrill AR, Sexton PM, Christopoulos A, Conn J, Lindsley CW, Bradley SJ, Tobin AB, muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease. Sci Signal, 15(760):eabm3720(2022) [pubmed]

submitter keyword: G protein-coupled receptor, Alzheimer’s disease, neuroinflammation, Warwick_RTP, positive allosteric modulators, transcriptomic, prion disease, proteomic, neurodegeneration, neurodegenerative disease, M1 muscarinic acetylcholine receptor

Professor Andrew B. Tobin
contact affiliation	Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
contact email	andrew.tobin@glasgow.ac.uk
lab head
Andrew Bottrill
contact affiliation	University of Warwick
contact email	a.r.bottrill@gmail.com
dataset submitter

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.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD025561

PRIDE project URI

• PRIDE
  1. PXD025561
     1. Label: PRIDE project
     2. Name: Slowing prion disease via M1 muscarinic receptors is associated with reduced neuroinflammation and down-regulation of neurodegenerative disease markers