New Synthetic 3-Benzoyl-5-Hydroxy-2H-Chromen-2-One (LM-031) Inhibits Polyglutamine Aggregation and Promotes Neurite Outgrowth through Enhancement of CREB, NRF2, and Reduction of AMPKα in SCA17 Cell Models.
Chiung-Mei ChenWan-Ling ChenShu-Ting YangTe-Hsien LinShu-Mei YangWenwei LinChih-Ying ChaoYih-Ru WuKuo-Hsuan ChangGuey-Jen Lee-ChenPublished in: Oxidative medicine and cellular longevity (2020)
Spinocerebellar ataxia type 17 (SCA17) is caused by a CAG/CAA expansion mutation encoding an expanded polyglutamine (polyQ) tract in TATA-box binding protein (TBP), a general transcription initiation factor. Suppression of cAMP-responsive element binding protein- (CREB-) dependent transcription, impaired nuclear factor erythroid 2-related factor 2 (NRF2) signaling, and interaction of AMP-activated protein kinase (AMPK) with increased oxidative stress have been implicated to be involved in pathogenic mechanisms of polyQ-mediated diseases. In this study, we demonstrated decreased pCREB and NRF2 and activated AMPK contributing to neurotoxicity in SCA17 SH-SY5Y cells. We also showed that licochalcone A and the related in-house derivative compound 3-benzoyl-5-hydroxy-2H-chromen-2-one (LM-031) exhibited antiaggregation, antioxidative, antiapoptosis, and neuroprotective effects in TBP/Q79-GFP-expressing cell models. LM-031 and licochalcone A exerted neuroprotective effects by upregulating pCREB and its downstream genes, BCL2 and GADD45B, and enhancing NRF2. Furthermore, LM-031, but not licochalcone A, reduced activated AMPKα. Knockdown of CREB and NRF2 and treatment of AICAR (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside), an AMPK activator, attenuated the aggregation-inhibiting and neurite outgrowth promoting effects of LM-031 on TBP/Q79 SH-SY5Y cells. The study results suggest the LM-031 as potential therapeutics for SCA17 and probable other polyQ diseases.
Keyphrases
- protein kinase
- oxidative stress
- binding protein
- induced apoptosis
- nuclear factor
- skeletal muscle
- transcription factor
- toll like receptor
- single cell
- cell cycle arrest
- signaling pathway
- dna damage
- gene expression
- small molecule
- stem cells
- cell therapy
- cell death
- genome wide
- inflammatory response
- human health
- early onset
- drug delivery
- risk assessment
- immune response
- heat shock protein
- pi k akt
- drug induced