Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.
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.
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France.
Marie-José
MJ
Lecomte
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Département de Chirurgie Maxillo-Faciale, Paris, France.
Chloé
C
Bertolus
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France.
Julie
J
Santamaria
Molecular Imaging Research Center (MIRCen), CEA, 92265 Fontenay-aux-Roses, France.
Anne-Laure
AL
Bauchet
UMR 7179, CNRS and Muséum National d'Histoire Naturelle, Paris, France.
Marc
M
Herbin
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France.
Françoise
F
Saurini
Department of Pharmacology, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
Hidemi
H
Misawa
AP-HP, Hôpital Pitié-Salpêtrière, Département de Neurophysiologie Clinique, Paris, France.
Thierry
T
Maisonobe
AP-HP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Paris, France; UMR-678, Inserm-UPMC, Hôpital Pitié-Salpêtrière, Paris, France.
Pierre-François
PF
Pradat
Inserm UMR-S952, CNRS UMR 7224, UPMC Univ Paris 06, Paris, France.
Marika
M
Nosten-Bertrand
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France.
Jacques
J
Mallet
CRICM, CNRS UMR 7225, Paris, France; UPMC Univ Paris 06, UMR 7225, Paris, France; Inserm, UMR_S975, Paris, France. Electronic address: sylvie.berrard@inserm.fr.
Sylvie
S
Berrard
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology*; D009046:Motor Neurons / Q000145:classification / Q000378:metabolism*; D053580:Muscle Strength / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors
C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine
Aging; Animal model; Choline acetyltransferase; Cholinergic; Conditional knockout mice; Late-onset neuromuscular defects; Motor neuron dysfunction; Post-polio