PXD032065

PXD032065 is an original dataset announced via ProteomeXchange.

Title	Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation.
Description	A growing body of evidence suggests that nuclear alpha-synuclein (aSyn) plays a role in the pathogenesis of Parkinson’s disease (PD). However, this question has been difficult to address as controlling the localization of aSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered Snca-NLS mice which localize endogenous aSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear aSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to aSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of Snca-NLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signalling, including Darpp32, Pde10a, and Gng7, which we further confirmed was decreased in cortical samples of the Snca-NLS mice compared to controls. These results suggest that chronic endogenous nuclear aSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of aSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2022-04-06
AnnouncementXML	Submission_2022-04-06_09:25:08.730.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD032065
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Haley Geertsma
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-05 04:56:23	ID requested
⏵ 1	2022-04-06 09:25:09	announced

Geertsma HM, Suk TR, Ricke KM, Horsthuis K, Parmasad JA, Fisk ZA, Callaghan SM, Rousseaux MWC, Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation. Hum Mol Genet, 31(21):3613-3628(2022) [pubmed]

submitter keyword: Mouse, brain, cortex, TMT10plex, LC-MS

Maxime Rousseaux
contact affiliation	Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
contact email	max.rousseaux@uottawa.ca
lab head
Haley Geertsma
contact affiliation	University of Ottawa
contact email	geertsma.haley@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/2022/04/PXD032065

PRIDE project URI

• PRIDE
  1. PXD032065
     1. Label: PRIDE project
     2. Name: Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation.