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

• DOI: 10.1038/s41467-021-25767-1
• Publication Date: 2021-09-10T10:03:22Z
• Authors: Debashis Dutta; Malabendu Jana; Moumita Majumder; Susanta Mondal; Avik Roy; Kalipada Pahan
• Keywords: Lewy Body Disease; Science; Primary Cell Culture; Article; Mice; 03 medical and health sciences; Animals; Humans; Promoter Regions, Genetic; Cells, Cultured; Mice, Knockout; 0303 health sciences; Dopaminergic Neurons; Q; NF-kappa B; Parkinson Disease; Multiple System Atrophy; Toll-Like Receptor 2; 3. Good health; Disease Models, Animal; Mutation; Myeloid Differentiation Factor 88; Mutagenesis, Site-Directed; alpha-Synuclein; Microglia; Signal Transduction

Abstract Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase association between TLR2 MyD88, resulting microglial activation. The TLR2-interaction domain MyD88 (wtTIDM) peptide-mediated selective inhibition reduces PFF-induced inflammation vitro. In PFF-seeded A53T mice, nasal administration wtTIDM peptide, NEMO-binding (wtNBD) or genetic deletion glial inflammation, decreases spreading, protects dopaminergic neurons by inhibiting NF-κB. summary, depends on TLR2/MyD88/NF-κB pathway it can be reduced delivery wtNBD peptides.