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.

Keywords: amyloid deposits; inflammasome; inflammation; myddosome; necrosome; neurodegenerative diseases; neurotoxicity; supramolecular organizing centers.

Figure 1

Amyloid-induced neurotoxicity mechanisms.

Figure 2

TLR signaling mediates formation of several neurotoxic products. (A) Myddosome. All TLRs’ but TLR3’s signaling cascades proceed through the association of MYD88, IRAK 4, and IRAK 1 or 2 into myddosome through death domain (DD) interactions. Subsequent signaling through TRAF6 can result in transcription factors NF-κB or AP-1 that both induce transcription of neurotoxic inflammatory mediators. (B) Triffosome. Upon activation of TLR3 or TLR4 on endosomes, TIR domain-containing adaptor protein inducing IFNβ (TRIF) oligomerizes through the TIR domain which allows the formation of triffosome, which comprised TNF receptor-associated factor 3 (TRAF3), TANK-binding kinase 1 (TBK1), and IκB kinase (IKK)-related kinase i (IKKi), or TRAF6. Activated TBK1 can phosphorylate interferon regulatory factor 3 (IRF3), thus inducing its dimerization and translocation to the nucleus where it binds to interferon-stimulated response elements and regulates transcription of type I interferons (IFN). TRIF can interact with receptor-interacting serine/threonine kinase 1 (RIP1) through the RIP homotypic interaction motif (RHIM) domain and induce either apoptosis or necroptosis and nuclear factor-kB (NF-kB) activation through the IKK complex.

Figure 3

Sensing of nucleic acids by RLR-MAVS and cGAS-STING pathway. Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are RIG-I-like receptors (RLR) that recognize cytosolic dsRNA and ssRNA. RLR filaments that form CARD tetramers associate with the CARD domain of mitochondrial antiviral signaling protein (MAVS) that is localized on the mitochondrial membrane and trigger its polymerization. Recruitment of TRAFs results in activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). Cyclic GMP–AMP synthase (cGAS) is a cytosolic dsDNA sensor, and when activated, cGAS catalyzes the formation of cGAMP that binds to stimulator of interferon genes (STING) residing on the endoplasmic reticulum (ER). Upon oligomerization, STING traffics from ER to Golgi apparatus (GA) leading to activation of transcription of proinflammatory cytokines such as IL-6, tumor necrosis factor (TNF) TNFα, and type I interferons (IFN).

Figure 4

Assembly and activation of inflammasomes. (A) Upon activation, the inflammasome sensor assembles into the inflammasome by recruiting adaptor protein ASC and effector protein pro-caspase-1. (B) In the nervous system, assembly of the NLRP3 inflammasome can be triggered by misfolded proteins such as amyloid-β, α-synuclein, tau oligomers, mutated SOD1, and PrP^Sc. Cytosolic protein aggregates can act in an autocrine fashion or upon cell death as extracellular stimuli. Upon inflammasome assembly, pro-caspase-1 is proteolytically cleaved. Activated caspase-1 in turn cleaves pro-IL-1β and pro-IL-18 into their active forms, and gasdermin D (GSDMD) to release the pore-forming N-terminal domain. IL-1β and IL-18 are released from the cell through GSDMD pores. Pyroptotic cell releases a number of other DAMPs.

Figure 5

Assembly and activation of RIP-associated SMOCs leading to necroptosis, apoptosis, or NF-κB activation. (A) Necrosome. Upon binding to the TNF receptor 1, TRADD, TRAF2 and 5, RIP-1, cIAPs, LUBAC, and other molecules are recruited to form Complex I, which promotes cell survival through activation of the NF-κB pathway. Following deubiquitylation of RIP1, Complex IIa or Complex IIb are formed, resulting in apoptosis or necroptosis, respectively. (B) Ripoptosome. This intracellular complex is composed of the RIP1, FADD, and caspase-8 and can switch between apoptosis and necroptosis.

Figure 6

Assembly and activation of apoptosome, PIDDosome, and DISC. (A) Apoptosome. Cytochrome c released from the mitochondria binds to Apaf-1, which enables Apaf-1 to bind dATP/ATP, followed by the conformational change that promotes apoptosome assembly. Next, the procaspase-9 is bound to the apoptosome and activated and the proteolytically active complex then activates effector caspases-3 and -7, resulting in intrinsic apoptosis. (B) DISC. The complex is comprised of death receptor, FADD, and procaspase-8/-10. Following autoproteolysis, active caspases cleave effector caspases-3 (-7) and induce apoptosis. (C) PIDDosome. This multiprotein complex is composed of PIDD1, RAIDD, and procaspase-2. Upon PIDDosome assembly, procaspase-2 is activated, which leads to apoptosis.