Charting the onset of Parkinson-like motor and non-motor symptoms in nonhuman primate model of Parkinson's disease.

Abstract

Parkinson's disease is a progressive neurodegenerative disease increasingly affecting our aging population. Remarkable advances have been made in developing novel therapies to control symptoms, halt or cure the disease, ranging from physiotherapy and small molecules to cell and gene therapy. This progress was enabled by the existence of reliable animal models. The nonhuman primate model of Parkinson's disease emulates the cardinal symptoms of the disease, including tremor, rigidity, bradykinesia, postural instability, freezing and cognitive impairment. However, this model is established through the specific loss of midbrain dopaminergic neurons, while our current knowledge reflects the reality of Parkinson's disease as a multisystem disease. Parkinson's disease involves both motor and non-motor symptoms, such as sleep disturbance, olfaction, gastrointestinal dysfunctions, depression and cognitive deficits. Some of the non-motor symptoms emerge earlier at the prodromal phase and worsen with disease progression, yet in basic and translational studies, they are rarely considered as endpoints. In this study, we set to characterize an ensemble of less described motor and non-motor dysfunctions in the marmoset MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model. We provide evidence that this animal model expresses postural head tremor and a progressive worsening of fine motor skills, movement coordination and cognitive abilities over a 6-month period. We report for the first time a non-invasive approach showing detailed analysis of daytime and nighttime sleep and circadian rhythm disturbance remarkably similar to Parkinson's disease patients. This study describes the incidence of tremors, motor and non-motor dysfunctions in a preclinical model and highlights the need for their consideration in translating effective new therapeutic approaches for Parkinson's disease.