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PROGSY SIGNED

Prosaposin and GPR37 in synucleinopathies

Total Cost €

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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.

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

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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