Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice.
OBJECTIVE
Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model.


METHODS
ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose.


RESULTS
mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters.


CONCLUSIONS
These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.
Marc
M
Gotkine
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Gotkine
G
Marc
Leah
L
Rozenstein
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Rozenstein
R
Leah
Ofira
O
Einstein
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Einstein
E
Ofira
Oded
O
Abramsky
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Abramsky
A
Oded
Zohar
Z
Argov
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Argov
A
Zohar
Hanna
H
Rosenmann
Agnes Ginges Center for Neurogenetics, Department of Neurology, Hebrew University-Hadassah Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel.
Rosenmann
R
Hanna
D000110:Acetylcholinesterase / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009388:Neostigmine / Q000008:administration & dosage; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D013482:Superoxide Dismutase
D016376:Oligonucleotides, Antisense; D009388:Neostigmine; D013482:Superoxide Dismutase; D000110:Acetylcholinesterase