Targeting the Inflammasome to Treat Parkinson's Disease
Neurodegenerative conditions, such as Parkinson's disease, are strongly connected to chronic inflammation of brain tissue. Unresolved inflammation is disruptive to tissue function in many ways, and the immune cells of the brain are tightly integrated into the normal functioning of neurons and their synaptic connections. It is thus an important goal for the research community to find ways to suppress excessive, unresolved inflammation without also disrupting necessary inflammatory signaling required for health and the normal operation of the immune system. Early immunomodulatory treatments are blunt tools, usually targeting a single signal molecule involved in inflammation, and can cause long term harm via suppression of the normal immune response. It is hoped that the inflammasome and its role in the regulation of inflammation will prove to be a better target.
Parkinson's disease (PD) is the second-most common neurodegenerative disease, predominantly affecting the elderly. The pathogenesis of PD contributed by both environmental and genetic factors is rather complex and not fully understood. The limited treatment options also add to its socioeconomic impact. Importantly, to date, no therapies are able to prevent or delay the disease progression. Thus, there is an enormous need to have a deeper understanding of PD pathogenesis and develop novel therapeutic approaches to improve the lives of PD patients.
Among the various novel approaches to manage PD, immunomodulation has gained much popularity recently. This approach is conceived based on the heavy involvement of the immune system in the pathogenesis and progression of PD. Neuroinflammation is one of the immune processes of paramount importance in PD. Reactive microglia increased significantly in the substantia nigra region of PD patients upon post-mortem examinations. Moreover, enhanced microglial activation was also observed in various PD animal models. Besides central nervous system (CNS) inflammation, peripheral inflammation is also believed to play a pivotal role in PD. Peripheral pro-inflammatory stimuli can be transported to the brain, activate the primed microglia, prompt neuroinflammation, and exacerbate disease progression.
An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.