Supramolecular organizing centers at the interface of inflammation and neurodegeneration

Abstract

The pathogenesis of neurodegenerative diseases involves the accumulation of misfolded protein aggregates. These deposits are both directly toxic to neurons, invoking loss of cell connectivity and cell death, and recognized by innate sensors that upon activation release neurotoxic cytokines, chemokines, and various reactive species. This neuroinflammation is propagated through signaling cascades where activated sensors/receptors, adaptors, and effectors associate into multiprotein complexes known as supramolecular organizing centers (SMOCs). This review provides a comprehensive overview of the SMOCs, involved in neuroinflammation and neurotoxicity, such as myddosomes, inflammasomes, and necrosomes, their assembly, and evidence for their involvement in common neurodegenerative diseases. We discuss the multifaceted role of neuroinflammation in the progression of neurodegeneration. Recent progress in the understanding of particular SMOC participation in common neurodegenerative diseases such as Alzheimer’s disease offers novel therapeutic strategies for currently absent disease-modifying treatments.

Spatially resolved multiomics on the neuronal effects induced by spaceflight

“…Cortical neurons (bottom layers; ST cluster 9) showed an abundance of DEGs (3208 in total; 1808 upregulated and 1400 downregulated) with functions related to neuronal development, and synaptic transmission in the bottom layers of cortex (somatosensory, motor, visual). Consensus pathway analysis 19 highlighted multiple neurodegeneration-associated pathways in Cortical neurons (bottom layers; ST cluster 9) and Choroid plexus and subventricular structures (ST cluster 16), including protein misfolding and abnormal protein clearance, mapping to neurodegenerative diseases characterized by protein misfolding and accumulation, such as Parkinson's disease, Alzheimer's disease and Huntington's disease 20,21 (Fig. 3D,E).…”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…As a result of ischemic brain damage, both the production of ROS, damaged tissues, and necrotic cells determine the trigger of an inflammatory response mediated by cells of innate immunity [ 20 , 21 ]. In addition, astrocytes, microglia, neurons, and endothelial cells release cytokines that secrete pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-18, accountable for neuronal and glial cell death following ischemic stroke [ 22 , 23 ].…”

“…NF-κB migrates into the cell’s nucleus, where it ties up DNA and initiates the transcription and translation of the precursor of IL-18 and IL-1β and of NLRP3 [ 58 ]. In the NF-κB signaling pathway, two signaling molecules such as MyD88 (Myeloid differentiation primary response 88) and TRIF (TIR-domain-containing adapter-inducing interferon-β) are implicated in the induction of NLRP3 inflammasome and pro-ILβ in response to ligands interacting with TLR4 [ 21 ]. In the MyD88-dependent pathway, MyD88, an adaptor molecule, binds to the cytoplasmic side of TLR4 with subsequent recruitment of IRAK-4 and IRAK-1 through death domains.…”

“…In the induction process during the priming phase, FADD and caspase 8 are also involved, as recent publications have shown. They are both apoptotic signaling molecules, but they play the role of induction regardless of their apoptotic properties [ 21 ]. Caspase-8 activates NF-κB by interacting with the IKK complex, while FADD can play a double role as it can activate or repress the NF-κB, stimulating apoptosis [ 63 ].…”

OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation

“…There are various types of SMOCs that are primarily associated with inflammation, such as NLRP3 inflammasome and Myddosome [ 9 ]. The Myddosome is an oligomeric complex that consists of the Myeloid differentiation primary response protein (MyD88) and Interleukin-1 Receptor-Associated Kinases (IRAK) family.…”