Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a neurological disorder affecting motor neurons and leading to progressive loss of voluntary muscle function, paralysis, and death
For global PGC-1α transgene expression driven by the actin promoter, the plasmid vector pCAGGS 20 containing the cytomegalovirus immediate-early (CMV-IE) enhancer and chicken β-actin promoter was modified by inserting a NotI site at the vector XbaI site and a SalI site at the vector HindIII site
As would be expected for a transgene expressed under the actin promoter, in the actin-PGC-1α mice, the transgene was expressed in all the tissues tested (Figure 2)
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a neurological disorder affecting motor neurons and leading to progressive loss of voluntary muscle function, paralysis, and death. Mitochondrial bioenergetics are increased in the neocortex of patients with fALS as compared to controls [3,4]. The SOD1G93A mutant, a commonly studied model of fALS, causes decreased mitochondrial respiration [6,7] and increased fragmentation of the organelle [8] compared to wild-type controls, leading to loss of neurons in the anterior horn of the spinal cord [9]. Mitochondrial functional changes have been reported in sALS, including reduced mitochondrial respiration in skeletal muscle [11] and fibroblasts [12], increased bioenergetic function in fibroblasts [13], but no alteration in mitochondrial respiration in the spinal cord [4]. Mitochondrial abnormalities may represent a disease mechanism shared by both sALS and fALS [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
