Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics
27 Pages Posted: 28 Mar 2019More...
Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of voluntary muscle function due to death of motor neurons. Energy metabolism deficits at the level of mitochondrial function have been implicated in the pathogenesis of ALS. We have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a regulator of mitochondrial biogenesis. As pharmacological intervention targeting PGC-1α would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1α is beneficial in the ALS mouse model.
Methods: We generated transgenic mice with PGC-1α transgene expression driven by the actin promoter. Transgene expression was confirmed by PCR.
Findings: The wild-type, actin-PGC-1α, SOD1G93A and actin-PGC-1α/SOD1G93A mice generated by crossing the actin-PGC-1α and SOD1G93A transgenic lines were monitored for weight loss, motor performance by accelerating rotarod test and survival. Interestingly, there was no significant improvement in body weight, motor function or survival in SOD1G93A mice over-expressing actin-PGC-1α.
Interpretation: Our previous studies showed, in the same mouse model, that PGC-1α ectopic expression under the NSE promoter significantly improved motor function and survival. A potential explanation for this difference is that the actin promoter does not induce, in the cells that are specifically relevant in mechanisms associated with ALS pathology, levels of PGC-1α relevant to disease pathophysiology. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons.
Funding: This study was supported by discretionary funding to GMP . Dr. Pasinetti holds a Senior VA Career Scientist Award.
Declaration of Interest: No conflicts of interest exist for any of the authors.
Ethical Approval: All animal protocols used in the study were approved by the Institutional Animal Care and Use Committee of the Icahn School of Medicine at Mount Sinai.
Keywords: mitochondrial biogenesis, motor function, neurodegeneration, tissue-specific expression
Suggested Citation: Suggested Citation