The tree shrew model of Parkinson's disease: A cost-effective alternative to non-human primate models.

The surge in demand for experimental monkeys has led to a rapid increase in their costs. Consequently, there is a growing need for a cost-effective model of Parkinson's disease (PD) that exhibits all core clinical and pathological phenotypes. Evolutionarily, tree shrews (Tupaia belangeri) are closer to primates in comparison to rodents and could be an ideal species for modeling PD. To develop a tree shrew PD model, we used the 1-methyl-4-phenylpyridinium (MPP⁺), a metabolite derived from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to induce lesions in dopaminergic neurons of the unilateral substantia nigra. The induced tree shrew model consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms included bradykinesia, rest tremor, postural instability, and about 50% individuals showed apomorphine-induced rotations, a classic phenotype of unilateral PD models. All these are closely resembled the ones observed in PD monkeys. Meanwhile, this model was also sensitive to L-dopa treatment with a dose dependent manner, which suggested that the motor deficits are dopamine dependent. Immunostaining showed a significant loss of dopaminergic neurons (approximately 95%) in the lesioned substantia nigra, which is a crucial PD pathological marker. Moreover, a control group of nigral saline injection did not show any motor deficits and pathological changes. Cytomorphological analysis revealed that the size of nigral dopaminergic neurons in tree shrews is much bigger than that of rodents and is close to that of macaques. The morphological similarity may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, in this study we have successfully developed a PD model in a small animal species that faithfully recapitulated the classic clinical symptoms and key pathological indicators of PD monkeys, providing a novel and low-cost avenue for evaluation of PD treatments and underlying mechanisms.