PROGSY SIGNED
Prosaposin and GPR37 in synucleinopathies
Total Cost €
0EC-Contrib. €
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Project "PROGSY" data sheet
The following table provides information about the project.
| Coordinator |
KAROLINSKA INSTITUTET
Organization address contact info |
| 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.
| # | ||||
|---|---|---|---|---|
| 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 |
|---|---|---|---|
| 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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