Department of Pharmacology and Chemical Biology

Neuronal Mechanisms Underlying Sex Differences in Parkinson’s Disease and Dystonia

Biological sex has a strong influence on the pathogenesis and clinical features of both Parkinson’s disease and dystonia. Males are two times more likely to develop PD whereas females exhibit more severe side effects in response to L-DOPA treatment than males. The risk for developing dystonia also varies by sex with females 2-3x more likely to develop dystonia than males. Although it has been known for decades that biological sex is a risk factor for both Parkinson's disease and dystonia, very little work has focused on the underlying mechanisms However, anecdotal clinical evidence supports a role for estrogens. It is known that estrogen receptors are expressed in the basal ganglia, a locus of dysfunction in both Parkinson’s disease and dystonia, but the effects of estrogen at both the molecular and physiologic levels are unknown. In fact, the neuronal subtypes that express estrogen receptors remains largely unknown. The goal of our research is to fill these gaps in knowledge by using spatial transcriptomics, calcium imaging in awake behaving mice, behavioral analyses and pharmacological challenges to understand how ovarian hormones affect basal ganglia function in health and disease. Ultimately, our work will provide foundational knowledge that has direct implications for prognosis and therapeutic strategies tailored specifically to the unique needs of females and males.

Our research is focused on the following specific questions:

1) What is the role of ovarian hormones in the presentation of Parkinson's disease and dystonia?

2) How does the molecular signature (transcriptome) of Parkinson's disease and dystonia differ between males and females and what is the role of ovarian hormones?

3) How does neuronal activity (in vivo calcium imaging) in Parkinson's disease and dystonia differ between males and females and what is the role of ovarian hormones?

4) Can we identify therapeutic strategies targeted specifically toward females or males?