Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
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Abbreviations
- AD
- Alzheimer’s Disease
- DR5
- direct repeats spaced by 5 nucleotides
- AQ
- amodiaquine
- EAE
- experimental autoimmune encephalomyelitis
- GFP
- green fluorescent protein
- HBA
- number of hydrogen-bond acceptor
- HBD
- number of hydrogen-bond donor
- HTRF
- homogenous time-resolved fluorescence resonance energy transfer
- KEGG
- Kyoto encyclopedia of genes and genomes
- LBD
- ligand binding domain
- MPTP
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin
- MS
- multiple sclerosis
- NBRE
- NGFI-B response element
- NCoA6
- nuclear receptor co-activator 6
- NCoR-1
- nuclear receptor co-repressor 1
- NCoR-2
- nuclear receptor co-repressor 2
- NR
- nuclear receptor
- NRIP1
- nuclear receptor interacting protein 1
- NSAIDs
- non-steroidal anti-inflammatory drugs
- Nurr1
- nuclear receptor related 1
- NurRE
- Nur-response element
- PAINS
- pan assay interference compounds
- PD
- Parkinson’s Disease
- POMC
- pro-opiomelanocortin
- PPAR
- peroxisome proliferator-activated receptor
- qRT-PCR
- quantitative real-time polymerase chain reaction
- RAR
- retinoic acid receptor
- RT
- room temperature
- RXR
- retinoid X receptor
- SD
- standard deviation
- S.E.M.
- standard error of the mean
- TPSA
- topological polar surface area
- TR-FRET
- time-resolved fluorescence resonance energy transfer.