Selective disruption of acetylcholine synthesis in subsets of motor neurons: A new model of late-onset motor neuron disease

Marie José Lecomte, Chloé Bertolus, Julie Santamaria, Anne Laure Bauchet, Marc Herbin, Françoise Saurini, Hidemi Misawa, Thierry Maisonobe, Pierre François Pradat, Marika Nosten-Bertrand, Jacques Mallet, Sylvie Berrard

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~. 40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology.

Original languageEnglish
Pages (from-to)102-111
Number of pages10
JournalNeurobiology of Disease
Volume65
DOIs
Publication statusPublished - 2014 May

Fingerprint

Motor Neuron Disease
Motor Neurons
Acetylcholine
Choline O-Acetyltransferase
Phenotype
Gene Knockout Techniques
Muscle Strength
Poliomyelitis
Brain Stem
Weight Loss
Spinal Cord
Muscles
Enzymes
Genes

Keywords

  • Aging
  • Animal model
  • Choline acetyltransferase
  • Cholinergic
  • Conditional knockout mice
  • Late-onset neuromuscular defects
  • Motor neuron dysfunction
  • Post-polio

ASJC Scopus subject areas

  • Neurology

Cite this

Lecomte, M. J., Bertolus, C., Santamaria, J., Bauchet, A. L., Herbin, M., Saurini, F., ... Berrard, S. (2014). Selective disruption of acetylcholine synthesis in subsets of motor neurons: A new model of late-onset motor neuron disease. Neurobiology of Disease, 65, 102-111. https://doi.org/10.1016/j.nbd.2014.01.014

Selective disruption of acetylcholine synthesis in subsets of motor neurons : A new model of late-onset motor neuron disease. / Lecomte, Marie José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie.

In: Neurobiology of Disease, Vol. 65, 05.2014, p. 102-111.

Research output: Contribution to journalArticle

Lecomte, MJ, Bertolus, C, Santamaria, J, Bauchet, AL, Herbin, M, Saurini, F, Misawa, H, Maisonobe, T, Pradat, PF, Nosten-Bertrand, M, Mallet, J & Berrard, S 2014, 'Selective disruption of acetylcholine synthesis in subsets of motor neurons: A new model of late-onset motor neuron disease', Neurobiology of Disease, vol. 65, pp. 102-111. https://doi.org/10.1016/j.nbd.2014.01.014
Lecomte, Marie José ; Bertolus, Chloé ; Santamaria, Julie ; Bauchet, Anne Laure ; Herbin, Marc ; Saurini, Françoise ; Misawa, Hidemi ; Maisonobe, Thierry ; Pradat, Pierre François ; Nosten-Bertrand, Marika ; Mallet, Jacques ; Berrard, Sylvie. / Selective disruption of acetylcholine synthesis in subsets of motor neurons : A new model of late-onset motor neuron disease. In: Neurobiology of Disease. 2014 ; Vol. 65. pp. 102-111.
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