Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo

Pathways to control the spreading of alpha-synuclein (alpha-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 alpha-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 alpha-syn spreading, and protects dopaminergic neurons by inhibiting NF-kappa B. In summary, alpha-syn spreading depends on the TLR2/MyD88/NF-kappa B pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides. The mechanisms underlying the spreading of alpha-synuclein in various alpha-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-kappa B pathway can reduce alpha-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models

Automated summary

Targeting the TLR2/MyD88/NF-kappa B pathway can reduce alpha-synuclein spreading, decrease neuroinflammation, and protect dopaminergic neurons.