Abstract
Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase the association between TLR2 and MyD88, resulting in microglial activation. The TLR2-interaction domain of MyD88 (wtTIDM) peptide-mediated selective inhibition of TLR2 reduces PFF-induced microglial inflammation in vitro. In PFF-seeded A53T mice, the nasal administration of the wtTIDM peptide, NEMO-binding domain (wtNBD) peptide, or genetic deletion of TLR2 reduces glial inflammation, decreases α-syn spreading, and protects dopaminergic neurons by inhibiting NF-κB. In summary, α-syn spreading depends on the TLR2/MyD88/NF-κB pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides.
Highlights
Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear
To monitor preformed α-syn fibrils (PFF)-induced TLR2 activation in microglia, mouse BV-2 microglial cells were treated with PFF, and TLR2-MyD88 interaction was evaluated by immunoprecipitation-coupled western blot
While the DNA-binding activity of NF-κB was evaluated by the formation of a distinct and specific complex in electrophoretic mobility shift assay (EMSA), the transcriptional activity of NF-κB was monitored by the expression of luciferase from a reporter construct, pNF-κB-Luc
Summary
Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. We found that microglia-derived proinflammatory molecules increased neuronal α-syn expression via NF-κBdependent transcriptional events and that blocking NF-κB activation in the brain by nasal NEMO-binding domain (NBD) peptide decreased α-syn spreading and protected DAergic neurons in PFF-seeded A53T mice. These results suggest that the TLR2/MyD88/NF-κB pathway plays an important role in α-syn spreading and that targeting this pathway may have therapeutic importance for different α-synucleinopathies such as PD, MSA, and DLB
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have