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

Author

Listed:
  • 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
    Division of Research and Development, Jesse Brown Veterans Affairs Medical Center)

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.

Suggested Citation

  • Debashis Dutta & Malabendu Jana & Moumita Majumder & Susanta Mondal & Avik Roy & Kalipada Pahan, 2021. "Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25767-1
    DOI: 10.1038/s41467-021-25767-1
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