RT Journal Article
SR Electronic
T1 Nurr1 modulation mediates neuroprotective effects of statins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.15.460433
DO 10.1101/2021.09.15.460433
A1 Sabine Willems
A1 Whitney Kilu
A1 Giuseppe Faudone
A1 Jan Heering
A1 Daniel Merk
YR 2021
UL http://biorxiv.org/content/early/2021/09/16/2021.09.15.460433.abstract
AB The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here we report pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects have been demonstrated. Several statins directly affected Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies. Simvastatin exhibited anti-inflammatory effects in astrocytes which were abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1 silenced cells revealed strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induced several neuroprotective mechanisms via Nurr1, for example, in energy utilization and reduced apoptosis. These findings suggest Nurr1 involvement in the well-documented but mechanistically elusive neuroprotection by statins.Competing Interest StatementThe authors have declared no competing interest.ADAlzheimer’s DiseaseDR5direct repeats spaced by 5 nucleotidesAQamodiaquineEAEexperimental autoimmune encephalomyelitisGFPgreen fluorescent proteinHBAnumber of hydrogen-bond acceptorHBDnumber of hydrogen-bond donorHTRFhomogenous time-resolved fluorescence resonance energy transferKEGGKyoto encyclopedia of genes and genomesLBDligand binding domainMPTP1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinMSmultiple sclerosisNBRENGFI-B response elementNCoA6nuclear receptor co-activator 6NCoR-1nuclear receptor co-repressor 1NCoR-2nuclear receptor co-repressor 2NRnuclear receptorNRIP1nuclear receptor interacting protein 1NSAIDsnon-steroidal anti-inflammatory drugsNurr1nuclear receptor related 1NurRENur-response elementPAINSpan assay interference compoundsPDParkinson’s DiseasePOMCpro-opiomelanocortinPPARperoxisome proliferator-activated receptorqRT-PCRquantitative real-time polymerase chain reactionRARretinoic acid receptorRTroom temperatureRXRretinoid X receptorSDstandard deviationS.E.M.standard error of the meanTPSAtopological polar surface areaTR-FRETtime-resolved fluorescence resonance energy transfer.