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.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Disease Models, Animal
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Dopaminergic Neurons / immunology
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Dopaminergic Neurons / metabolism*
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Humans
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Lewy Body Disease / genetics
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Lewy Body Disease / pathology
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Mice
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Mice, Knockout
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Microglia / immunology
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Microglia / metabolism
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Microglia / pathology*
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Multiple System Atrophy / genetics
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Multiple System Atrophy / pathology
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Mutagenesis, Site-Directed
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Mutation
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / metabolism
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Parkinson Disease / genetics
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Parkinson Disease / pathology
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Primary Cell Culture
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Promoter Regions, Genetic
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Signal Transduction / immunology
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism*
Substances
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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SNCA protein, human
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Snca protein, mouse
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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alpha-Synuclein