Translational studies of molecular interactions in Parkinson’s disease

Interactions between molecules are the basis of cellular function. In disease, these tightly regulated systems are often disturbed. Parkinson’s disease (PD) is recognized by protein aggregates in the brain of erroneously interacting molecules, directly linking the clinical picture to the molecular mechanisms. The currently incomplete understanding of the mechanisms behind PD pathogenesis impedes the development of disease-modifying treatment and new targets are needed since today’s dopaminergic treatment does not fully alleviate the symptoms. G protein-coupled receptors (GPCRs) are a wide group of transmembrane receptors usually targeted by drugs due to their ability to convey extracellular information into definite cellular responses. This Thesis focuses on protein interactions, from cellular models of a Parkinson-linked GPCR, GPR37, to detection of nanoaggregates in serum from PD patients as a sign of disease.

The main findings relate to the interactome of GPR37 as a factor regulating cell survival. GPR37 has been suggested to accumulate and cause dopaminergic cell death in PD when improperly folded but is able to elicit cytoprotective function when correctly matured and trafficked to the cell surface. We report that GPR37 interaction with ganglioside GM1-enriched lipid rafts and a proposed ligand prosaposin affects trafficking of GPR37 to the plasma membrane. Since the role of lipids in PD pathogenesis is increasingly acknowledged and GM1 has been suggested to slow down PD progression in clinical studies, we further studied the mechanism of the GPR37-GM1 interaction. We propose that exogenous GM1 treatment increase cellular resistance to a neurotoxin partly through a GPR37-dependent mechanism. This suggests yet another molecular mechanism of GM1 cytoprotection. Moreover, GPR37 has been suggested to be a modulator of dopaminergic transmission why we investigated the proposed interaction with dopamine D2 receptor (D2R) and GPR37 in live cells. The levels of heterodimerization where generally low in our cellular system. However, it could be augmented both by chaperone treatment, inducing trafficking of GPR37, and by clinically used dopamine agonist treatment. Shifting the heterodimerization level of GPCRs is known to alter molecular response. Therefore, the physiological outcome of this interaction needs to deciphered to understand effects and side effects of dopamine agonist treatment.

We also investigate improper protein interactions as a potential biomarker in serum from PD patients by detection of β-sheet enriched nanoaggregates. We report a higher detected frequency of nanoamyloids in patients compared to healthy controls and a bimodal distribution of amyloid size in serum. However, the frequency of nanoamyloids did not correlate robustly with neither disease progression or disease symptoms. Potentially this is due to heterogeneity, both clinical and molecular, in the disease. This emphasizes the need of understanding the molecular interactions in a clinical context.

List of scientific papers

I. Gregorsson Lundius E, Vukojević V, Hertz E, Stroth N, Cederlund A, Hiraiwa M, Terenius L, Svenningsson P. GPR37 Protein Trafficking to the Plasma Membrane Regulated by Prosaposin and GM1 Gangliosides Promotes Cell Viability. Journal of Biological Chemistry. (2014) 289(8), 4660-73.
https://doi.org/10.1074/jbc.M113.510883

II. Hertz E, Terenius L, Vukojević V, Svenningsson P. GPR37 and GPR37L1 Differently Interact With Dopamine 2 Receptors in Live Cells. Neuropharmacology. (2019) 152, 51-57.
https://doi.org/10.1016/j.neuropharm.2018.11.009

III. Hertz E., Saarinen M., Svenningsson P. GM1 is Cytoprotective in GPR37-Expressing Cells and Down Regulates Signaling. [Manuscript]

IV. Hertz E., Tiiman A*, Terenius L, Vukojević V, Svenningsson P. Increased Amyloid Nanoplaques in Serum from Patients with Parkinson’s Disease. [Manuscript]