Effect of mitochondrial transcription factor a overexpression on motor neurons in amyotrophic lateral sclerosis model mice

J Neurosci Res. 2012 Jun;90(6):1200-8. doi: 10.1002/jnr.23000. Epub 2012 Feb 22.


Increasing evidence indicates that oxidative stress is an important mechanism underlying motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). Mitochondrial DNA (mtDNA) is highly susceptible to oxidative damage and has little potential for repair, although mitochondrial transcription factor A (TFAM) plays essential roles in maintaining mitochondrial DNA by reducing oxidative stress, promoting mtDNA transcription, and regulating mtDNA copy number. To analyze a possible therapeutic effect of TFAM on ALS pathology, double transgenic mice overexpressing G93A mutant SOD1 (G93ASOD1) and human TFAM (hTFAM) were newly generated in the present study. Rotarod scores were better in G93ASOD1/hTFAM double-Tg mice than G93ASOD1 single-Tg mice at an early symptomatic stage, 15 and 16 weeks of age, with a 10% extension of the onset age in double-Tg mice. The number of surviving MNs was 30% greater in double-Tg mice with end-stage disease, at 19 weeks, with remarkable reductions in the amount of the oxidative stress marker 8-OHdG and the apoptotic marker cleaved caspase 3 and with preserved COX1 expression. Double-immunofluorescence study showed that hTFAM was expressed specifically in MNs and microglia in the spinal cords of double-Tg mice. The present study suggests that overexpression of TFAM has a potential to reduce oxidative stress in MN and delay onset of the disease in ALS model mice. © 2012 Wiley Priodicals, Inc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Amyotrophic Lateral Sclerosis / mortality
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Caspase 3 / metabolism
  • Cell Count
  • Choline O-Acetyltransferase
  • DNA-Binding Proteins / metabolism
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Disease Models, Animal
  • Electron Transport Complex IV / metabolism
  • Gene Expression Regulation / genetics
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Proteins / metabolism*
  • Motor Neurons / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Spinal Cord / pathology*
  • Superoxide Dismutase / genetics
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • TFAM protein, human
  • Transcription Factors
  • 8-Hydroxy-2'-Deoxyguanosine
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Electron Transport Complex IV
  • Choline O-Acetyltransferase
  • Caspase 3
  • Deoxyguanosine