Pathobiology of neuroinflammation and basal ganglia circuitry in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and the most common movement disorder. A defining pathologic feature of PD is the progressive death of dopaminergic neurons in a basal ganglia nucleus termed the substantia nigra (SN). Another hallmark feature of PD pathology is the presence of Lewy bodies and Lewy neurites, which are cellular inclusions with aggregated protein depositions, representing pathology in neuronal cell bodies and neuritic processes. Recently, epidemiological and genetic studies support roles for neuroinflammation in the progression of PD. Two types of cells that play a critical role in regulating neuroinflammation are microglia and astrocytes, which are activated in the basal ganglia of PD patients. Studies within this dissertation characterized activation of microglial cells by alpha-synuclein (α-synuclein), the most abundant protein in Lewy bodies, which has been implicated in PD pathogenesis. To garner insights into molecular mechanisms associated with astrocyte proliferation and activation, genomic alterations during developmental stages of astrocytes were examined since they are likely to recapitulate the reactivity associated with gliosis in PD brain. The activation of these glial cells and pathology of neurons in the basal ganglia causes the hallmark symptoms of PD. The symptoms of PD are termed parkinsonism. These are thought to result, at least in part, from alterations in the balance of output of the neostriatal efferent neurons, due to the loss of dopaminergic neuronal innervation of these cells. Phosphodiesterase 10A (PDE10A) is preferentially expressed in neostriatal efferent pathways and PDE10A inhibitors (PDE10i) have been shown to target dopamine signaling mechanisms. Studies here have utilized PDE10i to understand the balance of activation of medium spiny neurons in the indirect pathway versus activation of the direct pathway, since recent findings show PDE10i lead to a decrease in thalamic drive to the motor cortex, a primary symptom of PD. In conclusion, the aims of this dissertation sought to identify neuroinflammatory mechanisms within activated microglia in response to α-synuclein and proliferating astrocytes. Also, this work evaluated an inhibition of PDE10A in neurons within a region important to the progression of PD.