title: Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.
abstract: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Uchida
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Mio
authors.initials: M
authors.lastname: Tajiri
authors.forename: Takuya
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.forename: Fumika
authors.initials: F
authors.lastname: Sakaue
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kanai
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirai
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Sano
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Shibuya
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Mariko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yokota
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kubodera
authors.forename: Masaki
authors.initials: M
authors.lastname: Tomori
authors.forename: Kyohei
authors.initials: K
authors.lastname: Sakaki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Enomoto
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hirai
authors.forename: Jiro
authors.initials: J
authors.lastname: Kumagai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yasutomi
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchihara
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D055316:Cystatin C / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000229:Dependovirus; D004195:Disease Models, Animal; D004576:Electromyography; D055724:Electrophysiological Phenomena; D005822:Genetic Vectors; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology; D016501:Neurites / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013045:Species Specificity; D013116:Spinal Cord / Q000378:metabolism; D013238:Stereotaxic Techniques
chemical_list: D055316:Cystatin C; D004268:DNA-Binding Proteins