Non-methylation-Linked Mechanism of REST-Induced Neuroglobin Expression Impacts Mitochondrial Phenotypes in a Mouse Model of Amyotrophic Lateral Sclerosis

Publication date: Available online 31 May 2019Source: NeuroscienceAuthor(s): Zoë P. Van Acker, Ken Declerck, Evi Luyckx, Wim Vanden Berghe, Sylvia DewildeAbstractNeuroglobin (Ngb) is a REST/NRSF-regulated protein, active in reactive oxygen species detoxification and cytochrome c inhibition, which provides a beneficial outcome in pathologies as Alzheimer's disease and strokes. Considering that oxidative stress and cell death are typical hallmarks of amyotrophic lateral sclerosis (ALS), we sought to explore Ngb's involvement along this disease progression. Ngb transcription was detected to be 2-fold down-regulated in late-stage SODG93A mice, similarly as previously described for Alzheimer disease. Interestingly, in accordance with REST/NRSF transcription, Ngb expression is higher in spinal cords than in cortices. Hence, downstream REST/NRSF mechanisms were studied. A methylation cluster in Ngb's exon 1 (Chr12:87101763–87,102,586) was selected to assess methylation alterations, based on significantly altered positions in GEO DataSets of human c9orf72 and sporadic ALS cases. However, only the methylation percentage on position Chr12.87102586 was significantly increased in SODG93A mice. A larger impact can therefore be expected from the detected altered REST splicing; with levels of alternatively spliced, gene-activating REST4 to be lower than those of the gene-inhibitory full variant. To look further into the link between Ngb and ALS, we generated a double mutant Ngb−/-SODG9...

Source: Neuroscience - June 1, 2019 Category: Neuroscience Source Type: research