Unfolding Danger: Protein Misfolding, NLRP3 Inflammasome Activation, and the Prion-Like Propagation of ASC Specks in Neurodegenerative Diseases

Abstract Protein-misfolding neuropathic diseases are characterized by the accumulation in the central nervous system of misfolded proteins, whose irreversible change into beta-sheets sticky conformation facilitates the protein to form aggregates, which represent the main commonality shared by these disorders, including Prion diseases, Alzheimer’s disease, Parkinson's disease, Amyotrophic lateral sclerosis and Frontotemporal dementia. To explain the mechanisms through which protein misfolding and aggregation lead to the development of these diseases, at least three models have been proposed. Besides the widely accepted gain- or loss-of-function model for misfolded proteins, the inflammation model proposes that abnormal protein aggregates act as culprits causing chronic inflammatory response that leads to cell death. Historically, inflammatory events were viewed as result of toxicity from the inability of the cell to clear misfolded proteins. However, how misfolded proteins cause inflammation remains still an open issue. Given the current lack of an overarching view describing the connection between protein misfolding-related neurodegenerative diseases and the inflammasome, we aim to outline this relationship in the present review. We integrate recent insights into the mechanistic links between protein misfolding and NLRP3 inflammasome activation, highlighting the impact of the recently described “prionoid-activity” of ASC specks on the progression of different neurodegenerative misfolding diseases.