Parkinson´s disease (PD) is the most common movement disorder and affects 1 % of the population above 60 years of age. The related condition, Dementia with Lewy Bodies (DLB) is the second most common form of dementia. Since people are living longer, the prevalence of PD and DLB is set to rise dramatically in the future. In PD, progressive loss of dopaminergic neurons results in a number of symptoms including tremor, bradykinesia and rigidity. Today, there are several clinically used therapies which enhance dopamine function and thereby alleviate the main symptoms of PD, at least at the early stages. However, none of them can halt progression of the disease. At a subcellular level, PD and DLB are characterized by accumulation of intracellular protein aggregates called Lewy bodies. The main constituent of Lewy bodies is alpha-synuclein and, consequently, PD and DLB are referred to as synucleopathies. The next breakthrough in the treatment of PD will be aimed at slowing down disease progression based on insights into the underlying pathogenic process. The overall objective of this proposal is to examine the role of GPR37in relation to parkinsonism. GPR37 is a G protein coupled receptor which easily misfolds and is found in Lewy bodies. GPR37 has actually been reported to be a core component of Lewy bodies, suggesting that it may be involved in early pathological events of PD. Intriguingly, my laboratory has found that properly folded GPR37, located at the plasma membrane, exerts neuroprotection against parkinsonian toxins in cell lines. GPR37 has also been reported to be activated by the neuroprotective factor prosaposin. I have recently summarized the literature and posed key research questions on these topics (Leinartaité L, Svenningsson P. Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease. Trends Pharmacol Sci. 2017 Aug;38(8):749-760.)
The overall aim of this programme is to generate mechanistic insight into the role of prosaposin, GPR37 and GPR37L1 as novel diagnostics and targets for the development of neuroprotective pharmacological therapies against synucleopathies, particularly PD.