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NLRP3 inflammasome activation in dopamine neurons contributes to neurodegeneration in Parkinson’s Disease
Author(s) -
Panicker Nikhil,
Kam Tae-In,
Neifert Stewart,
Hinkle Jared,
Mao Xiaobo,
Karuppagounder Senthilkumar,
Wang Hu,
Kumar Manoj,
Pirooznia Sheila,
Pletnikova Olga,
Troncoso Juan,
Dawson Valina L.,
Dawson Ted M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01881
Subject(s) - parkin , pars compacta , substantia nigra , neurodegeneration , inflammasome , dopamine , neuroscience , programmed cell death , microbiology and biotechnology , parkinson's disease , biology , medicine , immunology , disease , pathology , dopaminergic , inflammation , apoptosis , genetics
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over a million people within the U.S. Underlying the clinical symptoms of PD is the degeneration of dopamine (DA) neurons located in the pars compacta of the substantia nigra (SNpc). Microglial activation of the NLRP3 inflammasome has been well‐documented in various neurodegenerative diseases, including PD. We report herein that adult onset conditional knockdown of Parkin in the mouse SNpc results in priming and activation of the NLRP3 inflammasome within dopamine neurons. These results were replicated in Parkin knockout generated human embryonic stem cell (hES) differentiated DA neurons (hDA neurons). Next, we utilized Nlrp3 A350VneoR mice to demonstrate that dopamine neuron specific activation of the NLRP3 inflammasome is sufficient to elicit DA neuron death. Double transgenic Parkin flx/flx /Casp1 KO mice were protected from adult onset Parkin deletion‐mediated DA neuron death. Finally, we demonstrate that Parkin is inactivated in alpha‐synuclein pre‐formed fibril (PFF)‐treated cortical neurons and in‐vivo, licensing neuronal NLRP3 inflammasome activation in sporadic PD mouse models as well. Taken together, our results indicate that atypical NLRP3 inflammasome activation within DA neurons may constitute a novel cell‐death mechanism that may contribute to neurodegeneration in PD. Support or Funding Information The first (and presenting) author is supported by a post‐doctoral fellowship from the Maryland Stem Cell Research Fund (MSCRF) Grant ID: 2017‐MSCRF‐3838