Abstract:
:α-Synuclein (α-syn) has been recognized to induce neuroinflammation and to disturb nerve repair process in Parkinson's disease. However, the potential mechanisms underlying α-syn-induced impairment of adult neurogenesis remain unclear. In the present study, A53T mutant α--synuclein transgenic (A53Ttg/tg) mice, caspase-1 knockout mice, and A53Ttg/tg;caspase-1-/- double transgenic mice were used to prepare adult neural stem cells (ANSCs) and to investigate inflammasome-related mechanism for α-syn-impaired neurogenesis in mouse subventricular zone (SVZ). We showed that α-syn inhibited neurogenesis in the SVZ of A53Ttg/tg mice and impaired proliferation and differentiation in ANSCs cultured in vitro, accompanied by reduced microRNA-7 (miR-7) expression levels. We further found that ANSC expressed NLRP3-containing inflammasome and α-syn activated both TLR4/NF-κB and NLRP3/caspase-1 signals in ANSCs. Either Nlrp3 knockdown or Caspase-1 knockout could attenuate the inhibition of proliferation in ANSCs induced by α-syn. Furthermore, we demonstrated that miR-7 post-transcriptionally controlled Nlrp3 expression besides targeting α-syn. Most notably, stereotactic injection of miR-7 mimics into lateral ventricles significantly inhibited NLRP3 inflammasome activation and improved adult neurogenesis in mouse SVZ. Our study provides a direct link between NLRP3 inflammasome activation and α-syn-impaired neurogenesis in the pathogenesis of α-synucleinopathies.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Fan Z,Lu M,Qiao C,Zhou Y,Ding JH,Hu Gdoi
10.1007/s12035-015-9620-5subject
Has Abstractpub_date
2016-12-01 00:00:00pages
7057-7069issue
10eissn
0893-7648issn
1559-1182pii
10.1007/s12035-015-9620-5journal_volume
53pub_type
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