UC San Diego

Unraveling a long-standing mystery behind Parkinson’s Disease (PD) has been a great interest to scientists over many decades and yet, the mechanisms and causes largely remain unknown. Some neuropathological hallmarks were discovered in the past decades, such as the accumulation of Lewy bodies and a degeneration of dopaminergic cells in substantia nigra pars compacta, and a dysfunction of the basal ganglia has been implicated in the development and progression of the disease. Specifically, the loss of dopaminergic cells leads to an overactivity in the indirect pathway relative to the direct pathway, and this imbalance ultimately causes a hyperinhibition of thalamic activities that manifests the most well-known Parkinsonian feature, resting tremor.

In this study, by knocking out a CDK5 gene from the Myf5 cell populations, an animal model with Parkinsonian symptoms was generated. The mutant animal was found to display a tremor event at 18-20 Hz, whereas wildtype animals showed its peak at 10-12Hz. Also, the tremor-displaying animals had a hyperactive movement, an increase in motor coordination and a reduction in muscular strength compared to the wild type animals. Next, a chemogenetic approach (DREADD) was used to activate the striatal Myf5 positive neurons, and the excitation successfully mimicked a phenotype of resting tremor, the most easily diagnosed and noticeable PD symptom, as well as the impairment in other motor functions as observed in the mutant animals. The study’s finding was further strengthened by in-vitro recordings of DREADD-injected, Myf5-Cre positive animals and by the optogenetics method, confirming that excitatory DREADD increases the neuronal excitabilities of the Myf5 cells and that a manipulation of striatal Myf5 cells is enough to induce a resting tremor. Moreover, mutant animals with CDK5 cKO in Myf5 cells had a higher number of hyperactive D1 MSNs than the number of hyperactive D2 MSNs, exhibiting a unique ratio of 2:1. Consistent with the previous finding, equivalently exciting D1 and D2 MSNs using the DREADD in RGS-Cre animals was not able to generate a Parkinson’s-like motor dysfunctions. Here, we elucidated an involvement of striatal Myf5 neurons and the imbalance of the direct and indirect pathways in the development of PD-related motor function deficits, and these findings will provide clues to investigating the etiology and pathogenesis of Parkinson’s disease.