title: Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice.
abstract: The target disconnection theory of amyotrophic lateral sclerosis (ALS) pathogenesis suggests that disease onset is initiated by a peripheral pathological event resulting in neuromuscular junction loss and motoneuron (MN) degeneration. Presymptomatic mSOD1(G93A) mouse facial MN (FMN) are more susceptible to axotomy-induced cell death than wild-type (WT) FMN, which suggests additional CNS pathology. We have previously determined that the mSOD1 molecular response to facial nerve axotomy is phenotypically regenerative and indistinguishable from WT, whereas the surrounding microenvironment shows significant dysregulation in the mSOD1 facial nucleus. To elucidate the mechanisms underlying the enhanced mSOD1 FMN loss after axotomy, we superimposed the facial nerve axotomy model on presymptomatic mSOD1 mice and investigated gene expression for death receptor pathways after target disconnection by axotomy vs. disease progression. We determined that the TNFR1 death receptor pathway is involved in axotomy-induced FMN death in WT and is partially responsible for the mSOD1 FMN death. In contrast, an inherent mSOD1 CNS pathology resulted in a suppressed glial reaction and an upregulation in the Fas death pathway after target disconnection. We propose that the dysregulated mSOD1 glia fail to provide support the injured MN, leading to Fas-induced FMN death. Finally, we demonstrate that, during disease progression, the mSOD1 facial nucleus displays target disconnection-induced gene expression changes that mirror those induced by axotomy. This validates the use of axotomy as an investigative tool in understanding the role of peripheral target disconnection in the pathogenesis of ALS.
authors.affiliation: Neuroscience Program, Loyola University Medical Center, Maywood, Illinois, 60153; Research and Development Service, Hines Veterans Administration Hospital, Hines, Illinois, 60141.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Haulcomb
authors.forename: Nichole A
authors.initials: NA
authors.lastname: Mesnard
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Batka
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Alexander
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Sanders
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Jones
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D019771:Axotomy; D016923:Cell Death / Q000502:physiology*; D018450:Disease Progression; D005154:Facial Nerve / Q000473:pathology / Q000503:physiopathology*; D065828:Facial Nucleus / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D019014:fas Receptor; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; MN; SOD1; facial nerve axotomy; gene expression; motoneuron