Microglial NLRP3 Inflammasome Mechanisms in Parkinson's and Other Neurodegenerative Diseases

Neurodegenerative diseases (NDs) like Parkinson’s (PD), Alzheimer’s (AD), and amyotrophic lateral sclerosis (ALS) are all characterized by several common molecular and cellular factors, including degeneration of neurons, pathological protein aggregation, and neuroinflammation. Neuroinflammation involves the response of the brain’s immune cells, known as microglia, to disease-associated (and other threatening) stimuli. One critical facet of the acute neuroinflammatory response that has been linked to the progressing pathologies of PD, AD, and ALS (as well as other NDs) is the recruitment and activation of the molecular immune signaling scaffold known as the NLRP3 inflammasome. Remaining “dormant” under normal conditions, the NLRP3 inflammasome is activated in response to the detection of various inflammatory stimuli, including many that apply to NDs, to amplify and broadcast pro-inflammatory signals and alert other cells to danger. However, if NLRP3 inflammasome activation proceeds unchecked in activated microglia, as often happens in NDs because of the ongoing presence of activating stimuli, it contributes to continued pathology and neurodegeneration by virtue of the inflammasome’s structure and downstream inflammatory signaling. The work in this thesis sheds light on differential activation mechanisms for the NLRP3 inflammasome, how they apply specifically to PD, AD, and ALS, and how they might be blocked, in particular by dopamine signaling. The data shown give rise to a hypothesis for the pathology of PD in particular in terms of NLRP3 inflammasome activation, dopamine inhibition, and selective vulnerability of dopaminergic neurons in the substantia nigra, the area of the brain most affected in this disease. Elucidating the role of the NLRP3 inflammasome in ND etiology, and how its modulation can help with ND amelioration or prevention, is crucial to improving our understanding of these diseases, leading to improved outcomes for patients.