Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention

Abstract

Most acute and chronic neurodegenerative conditions are accompanied by neuroinflammation; yet the exact nature of the inflammatory processes and whether they modify disease progression is not well understood. In this review, we discuss the key epidemiological, clinical, and experimental evidence implicating inflammatory processes in the progressive degeneration of the dopaminergic (DA) nigrostriatal pathway and their potential contribution to the pathophysiology of Parkinson's disease (PD). Given that interplay between genetics and environment are likely to contribute to risk for development of idiopathic PD, recent data showing interactions between products of genes linked to heritable PD that function to protect DA neurons against oxidative or proteolytic stress and inflammation pathways will be discussed. Cellular mechanisms activated or enhanced by inflammatory processes that may contribute to mitochondrial dysfunction, oxidative stress, or apoptosis of dopaminergic (DA) neurons will be reviewed, with special emphasis on tumor necrosis factor (TNF) and interleukin-1-beta (IL-1beta) signaling pathways. Epigenetic factors which have the potential to trigger neuroinflammation, including environmental exposures and age-associated chronic inflammatory conditions, will be discussed as possible 'second-hit' triggers that may affect disease onset or progression of idiopathic PD. If inflammatory processes have an active role in nigrostriatal pathway degeneration, then evidence should exist to indicate that such processes begin in the early stages of disease and that they contribute to neuronal dysfunction and/or hasten neurodegeneration of the nigrostriatal pathway. Therapeutically, if anti-inflammatory interventions can be shown to rescue nigral DA neurons from degeneration and lower PD risk, then timely use of anti-inflammatory therapies should be investigated further in well-designed clinical trials for their ability to prevent or delay the progressive loss of nigral DA neurons in genetically susceptible populations.

Fig. 1

Mechanisms and triggers that initiate and sustain microglia activation and contribute to dopaminergic neuron degeneration. Divergent disease initiation steps including neurotoxin exposure, traumatic brain injury, infection, and genetic mutations may converge to activate various cell types resulting in microgliosis, reactive astrocytosis, complement activation and production of autotoxic substances. This neuroinflammatory response may also include the involvement of components of the acquired immune response with the recruitment of autoreactive T cells and the production of auto-antibodies. As a result of immune system involvement, through both glial proliferation and complement activation, there is increased production of cytokines (in particular TNF, IL-1β, and IL-6), chemokines, proteases, ROS, and RNS to create an environment of increased inflammatory and oxidative stress in the SNpc that becomes self-sustaining. Alternatively, a healthy neuron may become dysfunctional as a result of genetic mutations that affect the ubiquitin proteasome system (UPS) or mitochondrial function which may sensitize DA neurons to epigenetic factors (i.e., oxidative neurotoxins, neuroinflammation). Subsequent exposures to neurotoxic agents and inflammatory insults can also act to hasten the degeneration and death of DA neurons. Regardless of the factor that causes the initial cell death, the resulting immune response contributes to an auto-amplifying cycle of microglial activation sustained by microglial-derived autocrine factors. Lastly, the presence of dying or dead DA neurons may be accompanied by the generation of unknown signals which target a neuron for phagocytosis by activated microglia. Self-perpetuating cycles of neuroinflammation and neurotoxicity in the nigra would ensure the progressive destruction of DA neurons as an individual ages.