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Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics

27 Pages Posted: 28 Mar 2019

See all articles by Merina Varghese

Merina Varghese

Mount Sinai Health System - Department of Neurology

Wei Zhao

Mount Sinai Health System - Department of Neurology

Shrishailam Yemul

Mount Sinai Health System - Department of Neurology

Prashant Vempati

Mount Sinai Health System - Department of Neurology

Aurelian Radu

Mount Sinai Health System - Department of Cell, Developmental, and Regenerative Biology

Sherry Simkovic

Mount Sinai Health System - Department of Neurology

Giulio Pasinetti

Mount Sinai Health System - Department of Neurology; James J. Peters Veterans Affairs Medical Center - Geriatric Research, Education and Clinical Center

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Abstract

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

Varghese, Merina and Zhao, Wei and Yemul, Shrishailam and Vempati, Prashant and Radu, Aurelian and Simkovic, Sherry and Pasinetti, Giulio, Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics (March 26, 2019). Available at SSRN: https://ssrn.com/abstract=3360101 or http://dx.doi.org/10.2139/ssrn.3360101

Merina Varghese

Mount Sinai Health System - Department of Neurology

New York, NY
United States

Wei Zhao

Mount Sinai Health System - Department of Neurology

New York, NY
United States

Shrishailam Yemul

Mount Sinai Health System - Department of Neurology

New York, NY
United States

Prashant Vempati

Mount Sinai Health System - Department of Neurology

New York, NY
United States

Aurelian Radu

Mount Sinai Health System - Department of Cell, Developmental, and Regenerative Biology

New York, NY
United States

Sherry Simkovic

Mount Sinai Health System - Department of Neurology

New York, NY
United States

Giulio Pasinetti (Contact Author)

Mount Sinai Health System - Department of Neurology ( email )

New York, NY
United States

James J. Peters Veterans Affairs Medical Center - Geriatric Research, Education and Clinical Center ( email )

Bronx, NY
United States

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