Explorations in Parkinson's Disease: A Systematic Examination of Aging Astrocyte Endfoot Calcium Dysregulation and Sex Specific Barriers in Developing Neuroprotective Treatments

Abstract

Parkinson’s disease is a multifaceted neurodegenerative disease characterized by dopamine neuron loss; but more importantly there are no know treatments for PD that can truly alter disease progression. The two major risk factors for PD are advanced age and male sex. It is in these risk factors that the key to developing effective neuroprotective drugs for men and women lies. To date, nearly all other age-related neurodegenerative diseases coincide with major changes to the blood brain barrier and brain vasculature in general. Astrocytes are one of the most numerous cells in the brain and regulate the BBB but remain critically under researched in health, aging, and disease. In this dissertation, I developed a model to study astrocyte endfoot Ca2+ signals across the lifespan to determine the extent to which endfoot Ca2+ events are altered by aging and most importantly in which stage of life these changes occur. Sex differences exist in every aspect of PD from disease susceptibility, severity, treatment efficacy. The basis for these differences likely lies in the baseline sex specific regulatory mechanisms within the nigrostriatal pathway. To address these points, I (i) developed a robust model of PD using a unilateral striatal lesion in male and female mice to test the neuroprotective effects of cytisine a smoking cessation drug and (ii) developed a model of surgical menopause prior to striatal lesion to further characterize the role of estrogen induce neuroprotection in PD.