REM sleep behavior and olfactory dysfunction: Enhancing the utility and translation of animal models in the search for precision medicines for Parkinson's disease

Parkinson's disease (PD) is a heterogeneous neurodegenerative disease that belongs to the family of synu-cleiopathies, varying according to age, symptoms and progression. The hallmark of the disease is the accumu-lation of misfolded alpha-synuclein (alpha-Syn) protein in neuronal and non-neuronal brain cells. Over the past decades, the diagnosis and treatment of PD had a view centred on motoric endpoint and deficits in the nigrostriatal dopaminergic system, and consequently animal models of PD with predominantly motor behavior deficits have been used to study the disease. However, clinical trials have failed to translate results from animal models into successful treatments. PD as a multisystem disorder therefore requires additional assessment of early non-motor symptoms. Braak's staging revealed early alpha-Syn pathology in the pontine brainstem and olfactory circuits controlling rapid eye movement sleep behavior disorder (RBD) and olfaction, respectively. Recent converging evidence from multicenter clinical trials points to RBD as the most important functional risk marker for prodromal PD and conducting neuroprotective therapeutic trials in RBD-enriched cohorts has been recom-mended. Animal models of RBD and olfactory dysfunction may help bridge the translational research gap in precision drug discovery for PD.