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Communication

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

1
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY 10468, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Biomolecules 2020, 10(5), 760; https://doi.org/10.3390/biom10050760
Received: 20 April 2020 / Revised: 8 May 2020 / Accepted: 11 May 2020 / Published: 13 May 2020
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1α has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1α as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1α under a neuron-specific enolase (NSE) promoter. 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 a SOD1G93A mouse model, by generating transgenic mice with PGC-1α transgene expression driven by an actin promoter. Actin-PGC-1α expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1α, wild-type, actin-PGC-1α, SOD1G93A, and actin-PGC-1α/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1α did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1α relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons. View Full-Text
Keywords: mitochondrial biogenesis; motor function; neurodegeneration; tissue-specific expression mitochondrial biogenesis; motor function; neurodegeneration; tissue-specific expression
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MDPI and ACS Style

Varghese, M.; Zhao, W.; Trageser, K.J.; Pasinetti, G.M. Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics. Biomolecules 2020, 10, 760. https://doi.org/10.3390/biom10050760

AMA Style

Varghese M, Zhao W, Trageser KJ, Pasinetti GM. Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics. Biomolecules. 2020; 10(5):760. https://doi.org/10.3390/biom10050760

Chicago/Turabian Style

Varghese, Merina, Wei Zhao, Kyle J. Trageser, and Giulio M. Pasinetti. 2020. "Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics" Biomolecules 10, no. 5: 760. https://doi.org/10.3390/biom10050760

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