Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model

Thomas M. Wengenack, Silvina S. Holasek, Carolina M. Montano, Dawn Gregor, Geoffry L. Curran, Joseph F. Poduslo

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)73-86
Number of pages14
JournalBrain Research
Volume1027
Issue number1-2
DOIs
StatePublished - Nov 19 2004
Externally publishedYes

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Anterior Horn Cells
Amyotrophic Lateral Sclerosis
Motor Neurons
Transgenic Mice
Cell Death
Nitric Oxide Synthase Type I
Superoxide Dismutase
Early Diagnosis
Lumbosacral Region
Mitogen-Activated Protein Kinase Kinases
p38 Mitogen-Activated Protein Kinases
Horns
Caspase 3
Spinal Cord
Therapeutics
Mutation
Enzymes

Keywords

  • Active caspase-3
  • Apoptosis
  • ASK1
  • nNOS
  • p38
  • SAPK/JNK

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. / Wengenack, Thomas M.; Holasek, Silvina S.; Montano, Carolina M.; Gregor, Dawn; Curran, Geoffry L.; Poduslo, Joseph F.

In: Brain Research, Vol. 1027, No. 1-2, 19.11.2004, p. 73-86.

Research output: Contribution to journalArticle

Wengenack, Thomas M. ; Holasek, Silvina S. ; Montano, Carolina M. ; Gregor, Dawn ; Curran, Geoffry L. ; Poduslo, Joseph F. / Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. In: Brain Research. 2004 ; Vol. 1027, No. 1-2. pp. 73-86.
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