Mechanisms of motor and non-motor complications in experimental parkinsonism

Parkinson’s disease (PD), one of the most common neurodegenerative disorders, is classically characterized by the progressive loss of midbrain dopaminergic neurons and by the emergence of cardinal motor symptoms including rigidity, tremor and bradykinesia. PD treatment relies on pharmacological dopamine replacement, which is the most effective therapy to alleviate motor symptoms. However, the use of L-Dopa and dopamine receptor agonists is associated with the development of motor and non-motor complications, such as dyskinesia and neuropsychiatric disorders, which can be even more debilitating than the cardinal symptoms of PD and represent a major limitation to its management. Utilizing experimental models of PD, the work presented in this thesis investigates the underlying mechanisms involved in these treatment-related complications.

In Paper I we examined changes in autophagy associated with L-Dopa-induced dyskinesia (LID), which consists of dystonic and choreic abnormal involuntary movements tending to occur within a few years from the beginning of L-Dopa treatment. We found that LID is associated with dopamine D1 receptor (D1R)-mediated accumulation of the autophagy- specific substrate p62, a marker of autophagy deficiency. Inhibition of the mammalian target of rapamycin complex 1 with rapamycin counteracted the impairment of autophagy produced by L-Dopa, and reduced dyskinesia, suggesting that autophagy-promoting agents may represent a novel pharmacological approach to the treatment of dyskinesia. In Paper II we examined the ability of pre- and post-surgical interventions to reduce the mortality observed in a bilateral 6-hydroxydopamine mouse model reproducing non-motor symptoms of PD. We showed that the survival rate of male and female mice subjected to this lesion differs significantly, with higher mortality among males, and provided a protocol of enhanced care, which nearly eliminates animal loss. The same model was utilized in Paper III to recapitulate features of dopamine dysregulation syndrome, a non-motor complication in PD patients associated with pathological overconsumption of dopaminergic medications, far beyond that necessary to correct motor disabilities. We found that L-Dopa acquires rewarding properties in dopamine-depleted mice and this effect was mediated by abnormal D1R transmission in the dorsal striatum. We identified ΔFosB as a potential target to counteract this condition.

Overall, the work presented in this thesis offers a new perspective on underlying, and potentially common, mechanisms involved in motor and non-motor complications induced by dopamine replacement therapy. These studies also reveal the importance of employing appropriate experimental models of PD to identify novel targets for therapeutic interventions.

List of scientific papers

I. Feyder, M., Plewnia, C. (co-first author), Lieberman, O. J., Spigolon, G., Piccin, A., Urbina, L., Dehay, B., Li, Q., Nilsson, P., Altun, M., Santini, E., Sulzer, D., Bezard, E., Borgkvist, A., & Fisone, G. Involvement of Autophagy in Levodopa-Induced Dyskinesia. Movement Disorders. 2021, 36(5):1137- 1146.
https://doi.org/10.1002/mds.28480

II. Masini, D., Plewnia, C., Bertho, M., Scalbert, N., Caggiano, V., Fisone, G. A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson's Disease for the Study of Non-Motor Symptoms. Biomedicines. 2021, 9(6):598.
https://doi.org/10.3390/biomedicines9060598

III. Plewnia, C., Masini, D., Fisone, G. Rewarding properties of L-Dopa in experimental parkinsonism are linked to dysregulated dopamine D1 receptor transmission. [Manuscript]