Upregulation Of PGC-1α In Neurons Protects Against Experimental Autoimmune Encephalomyelitis

Objective:increasing evidence shows that reactive oxygen species（ROS）generation and mitochondrial dysfunction are related to neuron loss in multiple sclerosis（MS）.Peroxisome proliferator-activated receptor-γco-activator-1α（PGC-1α）plays a pivotal role in modulating ROS levels,and regulates mitochondrial biogenesis and respiration.Here,we investigated the function of PGC-1αin experimental autoimmune encephalomyelitis（EAE）,a murine MS model.We hypothesize that reduced PGC-1αexpression plays a key role in the development of neurological damage and clinical symptoms,of MS,and rescue of PGC-1αin neurons protects them against MS-induced damage.Methods:we used wild-type（WT）mice to evaluate changes in PGC-1αprotein levels and key mitochondrial antioxidants and uncoupling proteins（UCPs）during the development of EAE.Transgenic mice with neuron-specific overexpression of PGC-1α(PGC-1α^f/f/Eno2-Cre)were used to explore how PGC-1αin neurons affects EAE outcome in terms of clinical symptoms and CNS demyelination.To evaluate the protective effect of PGC-1αin neurons,a neuronal cell line transfected with lentivirus harboring PGC-1αwas treated with E.coli lipopolysaccharide to mimic the EAE environment.RNA-seq analysis was employed to explore the potential target genes and signaling pathways.Results:In WT EAE mice,PGC-1αexpression was decreased at 13 d,followed by a steady decline up to 20 d,then modestly increased at 30 d..This pattern of PGC-1αexpression was accompanied by parallel alterations in levels of SOD2,Prx3,Trx2,and UCP4 and UCP5.Onset of clinical symptoms of PGC-1α^f/f/Eno2-Cre mice was delayed and less severe,and inflammation and demyelination in the spinal cord were reduced.Parallel increases in SOD2,Prx3,Trx2,and UCPs reduced the production of ROS,and inhibited apoptotic pathways.PGC-1α^f/f/Eno2-Cre mice had fewer apoptotic neurons compared to WT EAE mice.Overexpression of PGC-1αby lentivirus transfection in neuronal NSC-34 cells and stimulation with lipopolysaccharide showed similar results to those in vivo.RNA-seq analysis showed that apoptotic processes were significantly enriched in the top 10 significant GO terms of differentially expressed genes,and the apoptosis pathway was significantly enriched in KEGG pathway analysis.Interpretation:Our findings indicate that upregulation of neuronal PGC-1αprotected neurons from apoptosis in an MS animal model and in an in vitro model.Manipulating PGC-1αlevels in MS may be a fruitful approach in staving off this devastating disease and other neurodegenerative diseases.