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PROGSY SIGNED

Prosaposin and GPR37 in synucleinopathies

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EC-Contrib. €

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Partnership

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 PROGSY project word cloud

Explore the words cloud of the PROGSY project. It provides you a very rough idea of what is the project "PROGSY" about.

mechanistic    delineate    alpha    mice    grossly    membraneous    neurotoxic    agonism    intracellular    exceptional    autopsy    dopamine    hallmark    accumulation    gpcr    cellular    acute    constituent    insights    technological    regulates    co    neurotoxicity    label    trafficking    gba    contributions    interference    parkin    lbs    tracers    lrrk2    protein    psap    neurons    ligands    secreted    membrane    prosaptide    correlation    initiate    incl    transduced    neuroprotection    lysosomal    structures    atomic    stress    parkinson    survival    aggregated    fragment    enzyme    diagnosis    saposin    prosaposin    injury    spectroscopy    relative    aggregation    released    receptor    underlying    pet    molecule    synucleinopathies    normal    propensity    modeling    located    virally    lewy    pathological    progression    disease    dimer    examine    plasma    suggest    linked    pd    neurotrophic    versus    bodies    breakthrough    single    cgpr37ko    consistently    agonists    fluorescence    drug    multimerization    gpcrs    cue    anti    pathogenic    neuroprotective    synuclein    dopaminergic    gene    hypothesize    gpr37    treatment    advancements    dj    function    pivotal    unexpectedly    prosaptides   

Project "PROGSY" data sheet

The following table provides information about the project.

Coordinator
KAROLINSKA INSTITUTET 

Organization address
address: Nobels Vag 5
city: STOCKHOLM
postcode: 17177
website: www.ki.se

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Sweden [SE]
 Total cost 1˙950˙033 €
 EC max contribution 1˙950˙033 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-08-01   to  2020-07-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KAROLINSKA INSTITUTET SE (STOCKHOLM) coordinator 1˙950˙033.00

Map

 Project objective

The next breakthrough in the treatment of synucleinopathies, incl Parkinson´s disease (PD), will be aimed at interference of disease progression based on insights into the underlying pathogenic process. The pathological hallmark of PD are Lewy bodies (LBs), in which α-synuclein is the major constituent together with other PD-linked gene products (DJ-1, LRRK2, parkin, and GBA) and aggregated GPR37. GPR37 is exceptional among GPCRs having a high propensity for intracellular receptor accumulation and aggregation leading to neurotoxicity. However, unexpectedly, our results suggest that GPR37 is neuroprotective in dopaminergic when located at the plasma membrane. Consistently, prosaposin (PSAP), and its neurotrophic fragment prosaptide, were recently identified as agonists at GPR37. PSAP is a neuroprotective protein that regulates intracellular lysosomal enzyme function, with saposin C being a co-factor of GBA. In addition, we hypothesize that PSAP is secreted following cellular stress and, via membraneous GPR37, cue dopamine neurons to initiate survival pathways. Pivotal to this programme is modeling and analysis of the atomic structures of GPR37 in complex with prosaptide, which will grossly facilitate mechanistic understanding and drug development with potential use in diagnosis and treatment. Novel applications and technological advancements of fluorescence correlation spectroscopy will be implemented for single molecule trafficking of GPR37 and its ligands and will examine whether GPCR multimerization beyond dimer formation may be neurotoxic. Normal and cGPR37KO mice will be virally transduced by α-synuclein to delineate in the relative contributions of improved lysosomal function versus GPR37 agonism for neuroprotection by prosaptides. Evolving from the autopsy studies that anti–GPR37 label LBs and that prosaposin is released upon cellular injury, we will develop GPR37 ligands as PET tracers for LBs in synucleinopathies.

 Publications

year authors and title journal last update
List of publications.
2020 Zhang X, Mantas I, Fridjonsdottir E, Andrén PE, Chergui K and Svenningsson P
Deficits in motor performance, neurotransmitters and synaptic plasticity in elderly and experimental parkinsonian mice lacking GPR37
published pages: 84-89, ISSN: 1663-4365, DOI: 10.3389/fnagi
Frontiers in Aging Neuroscience 2020.00084 2020-04-01
2017 Cyril Monnot, Xiaoqun Zhang, Sahar Nikkhou-Aski, Peter Damberg, Per Svenningsson
Asymmetric dopaminergic degeneration and levodopa alter functional corticostriatal connectivity bilaterally in experimental parkinsonism
published pages: 11-20, ISSN: 0014-4886, DOI: 10.1016/j.expneurol.2017.02.014
Experimental Neurology 292 2019-06-07
2017 Leinartaité Lina, Svenningsson Per
Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease.
published pages: , ISSN: 0165-6147, DOI:
Trends in Pharmacological Sciences 2019-06-07

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