title: Spinal inhibitory interneuron pathology follows motor neuron degeneration independent of glial mutant superoxide dismutase 1 expression in SOD1-ALS mice.
abstract: Motor neuron degeneration and skeletal muscle denervation are hallmarks of amyotrophic lateral sclerosis (ALS), but other neuron populations and glial cells are also involved in ALS pathogenesis. We examined changes in inhibitory interneurons in spinal cords of the ALS model low-copy Gurney G93A-SOD1 (G1del) mice and found reduced expression of markers of glycinergic and GABAergic neurons, that is, glycine transporter 2 (GlyT2) and glutamic acid decarboxylase (GAD65/67), specifically in the ventral horns of clinically affected mice. There was also loss of GlyT2 and GAD67 messenger RNA-labeled neurons in the intermediate zone. Ubiquitinated inclusions appeared in interneurons before 20 weeks of age, that is, after their development in motor neurons but before the onset of clinical signs and major motor neuron degeneration, which starts from 25 weeks of age. Because mutant superoxide dismutase 1 (SOD1) in glia might contribute to the pathogenesis, we also examined neuron-specific G93A-SOD1 mice; they also had loss of inhibitory interneuron markers in ventral horns and ubiquitinated interneuron inclusions. These data suggest that, in mutant SOD1-associated ALS, pathological changes may spread from motor neurons to interneuronsin a relatively early phase of the disease, independent of the presence of mutant SOD1 in glia. The degeneration of spinal inhibitory interneurons may in turn facilitate degeneration of motor neurons and contribute to disease progression.
authors.affiliation: Department of Neuroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hossaini
authors.forename: Sebastian
authors.initials: S
authors.lastname: Cardona Cano
authors.forename: Vera
authors.initials: V
authors.lastname: van Dis
authors.forename: Elize D
authors.initials: ED
authors.lastname: Haasdijk
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Jan C
authors.initials: JC
authors.lastname: Holstege
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D000818:Animals; D064026:Calbindins; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D037502:Galectin 3 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology*; D009457:Neuroglia / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D064026:Calbindins; D037502:Galectin 3; D050487:Glycine Plasma Membrane Transport Proteins; D010320:Parvalbumins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C493270:Slc6a5 protein, mouse; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2