Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders

Abstract

Synucleinopathies, such as Parkinson’s disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded α-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric α-synuclein causes proinflammatory responses in the brain parenchyma by triggering microglial activation, which may exacerbate pathogenic processes by establishing a chronic neuroinflammatory milieu. Here, we found that higher-ordered oligomeric α-synuclein induced a proinflammatory microglial phenotype by directly engaging the heterodimer TLR1/2 (Toll-like receptor 1 and 2) at the cell membrane, leading to the nuclear translocation of NF-κB (nuclear factor κB) and the increased production of the proinflammatory cytokines TNF-α and IL-1β in a MyD88-dependent manner. Blocking signaling by the TLR1/2 heterodimer with the small molecule inhibitor, CU-CPT22, reduced the expression and secretion of these inflammatory cytokines from cultured primary mouse microglia. Candesartan cilexetil, a drug approved for treating hypertension and that inhibits the expression of TLR2, reversed the activated proinflammatory phenotype of primary microglia exposed to oligomeric α-synuclein, supporting the possibility of repurposing this drug for synucleinopathies.

Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies

“…Interestingly, in light of the recent evidence of the spreadinglike behavior of a-syn (discussed in the next section), recent studies have shown that recombinant a-syn is able to induce microglial activation and that microglial cells enhance a-syn toxicity in vitro (Daniele et al, 2015;Fellner et al, 2013;Zhang et al, 2005). Different assemblies of recombinant a-syn harbor distinct properties.…”

“…Modulation of this immune system activation has been reported beneficial in several in vitro and in vivo models of the disease (Brochard et al, 2009;Daniele et al, 2015).…”

“…Different assemblies of recombinant a-syn harbor distinct properties. While truncated a-syn has been reported to be the most potent inducer of microglial response (Fellner et al, 2013), another study reported that oligomeric but not monomeric forms of a-syn interact with TLR1/2 and induce morphofunctional activation of microglia (Daniele et al, 2015).…”

Drugging Membrane Protein Interactions

“…As measured by NF-κB reporter translocation and TNF secretion in primary mouse microglia, CU-CPT-22 attenuated the overactive microglial response. This finding demonstrates that TLR1/2 is a druggable target to treat neuroinflammation in synucleinopathies (109). …”

Bibenzyl compound 20c protects against endoplasmic reticulum stress in tunicamycin-treated PC12 cells in vitro

“…When IRE1 is activated, it catalyzes the splicing of the mRNA encoding the X-box-binding protein 1 (XBP1) to produce XBP1 and regulate target genes [8] . Although the mechanisms of PD pathogenesis remain unclear, many studies have indicated that the accumulation of α-syn may be a neurotoxic factor [9,10] . However, the mechanisms underlying α-syn accumulation and how α-syn accumulation contributes to neurodegeneration remain poorly understood.…”