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

Debashis Dutta, Malabendu Jana, Moumita Majumder, Susanta Mondal, Avik Roy and Kalipada Pahan ()
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Debashis Dutta: Rush University Medical Center
Malabendu Jana: Rush University Medical Center
Moumita Majumder: Rush University Medical Center
Susanta Mondal: Rush University Medical Center
Avik Roy: Rush University Medical Center
Kalipada Pahan: Rush University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25767-1

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