Neuroinflammation and the two-hit hypothesis of Parkinson's disease

Abstract

The ever-increasing prevalence of neurodegenerative diseases, Alzheimer's Disease (AD) and Parkinson's disease (PD), impose one the most significant medical and public health threats throughout the world. Characteristic PD symptoms include loss of voluntary motor control due to α-synuclein protein-aggregation, neuroinflammatory glial activation, mitochondrial dysfunction, oxidative stress, and progressive neuronal loss. There are currently no disease-modifying therapies for the disease nor has the etiology of PD been elucidated. Epidemiologic and experimental evidence suggests that genetic susceptibility, environmental pesticide exposure, and viral infections are possible risk-factors for PD, but a clear understanding of the environmental links to PD and how these factors can act in concert remains extremely limited. Research is beginning to shed light on neuroinflammation as a converging and coalescing pathway in the pathogenesis and pathophysiology of genetic, sporadic, and postencephalitic PD. While it has been appreciated since the late 1980s that brain inflammation is a hallmark of PD and other age-related neurodegenerative diseases, the immunological role of glia and the key trophic and inflammatory factors and pathways responsible for neurotoxicity and neuronal death in PD have not been clearly elucidated. Understanding how these pathways are regulated in glia during genetic, sporadic, and postencephalitic PD, and how they can directly or secondarily affect the onset and progression of PD is of keen interest. Therefore, the subject of this work will be to explore mechanisms by which glial cells modulate neuronal injury in genetic, sporadic, and postencephalitic cases of PD, with an emphasis on the role of neuroinflammatory activation of glia in single and two-hit models of PD.