Neuroinflammation and Oxidative Stress in Models of Parkinson’s Disease and Protein-Misfolding Disorders
Numerous mechanisms are implicated in the etiology of sporadic Parkinson’s disease (PD) including protein misfolding, oxidative stress and neuroinflammation, which contribute to the loss of dopaminergic neurons. Activation of glial cells exacerbates each of these mechanisms and there are currently no therapeutic agents that prevent damaging neuroinflammatory responses in microglia and astrocytes. Microglia are the resident macrophages of the CNS and can activate astrocytes, which are important for regulation of cerebral blood flow and neuronal metabolic homeostasis. Activated microglia and astrocytes strongly influence mechanisms of injury relevant to PD and are the primary sources of inflammatory and oxidative factors in the CNS. Glial cells can be activated endogenous and exogenous toxicants, as well as by misfolded proteins and other signals of neuronal stress. In animal models of PD and protein-misfolding disorders, oxidative and inflammatory mediators are produced and have been shown to induce loss of dopaminergic neurons. Delineating the molecular mechanisms that control the production of inflammatory and oxidative mediators from glial cells could provide new targets for therapeutic intervention to slow neurodegeneration relevant to PD and other disorders.