Receptor-mediated mechanisms in Parkinson´s disease and depression

This programme aims at providing better biomarkers anbd mechanism-based therapies for two common diseases: Parkinson´s disease (PD) and Major depressive disorder (MDD). Besides motor symptoms, many PD patients suffer from depression and dementia.

There are several symptomatic therapies towards motor symptoms of PD, but there is no therapy that slows down disease progression. GLP-1 agonists show promise as disease modifying therapies, but their mechanism of action are poorly understood. PD is characterized by accumulation of α-synuclein enriched Lewy bodies.

Misfolded GPR37 is a core component of Lewy bodies and induces dopamine neurodegeneration. Our unpublished data suggests that it is the cleaved N-terminus of GPR37 which accumulates in dopamine neurons. MDD is a leading cause of Disability Adjusted Life Years. The glutamate-based compound, s-ketamine, was recently approved as a fast acting antidepressant.

Psilocybin, a more classical psychedelic, which acts via serotonin G protein-coupled receptors (GPCRs) has also fast acting antidepressant properties.

Recent breakthroughs in revealing atomic resolution structures for GPCRs in complex with ligands and intracellular effectors enables functional understanding and in silico screening of molecules to GPCRs.

This translational programme will continue to reveal mechanisms whereby GPCRs, particularly GPR37, TAAR1 and GLP-1R, and a GPCR adaptor protein, p11, serves as biomarkers and therapy targets in PD and/or MDD.