A research group led by Professor Takanori Yokota and Chairman Hidehiro Mizusawa at Department of　Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University developed a non-human primate model of amyotrophic lateral sclerosis (ALS). This was achieved in cooperation with the research groups of Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tokyo Metropolitan Institute of Medical Science, and Chiba University. This work was supported by Comprehensive Research on Disability Health and Welfare; Research on Neurodegenerative Diseases/ALS from Ministry of Health, Labor and Welfare, Japan; Grant-in-Aid for Scientific Research (A) and Grant-in-Aid for Research Activity Start-up and Strategic Research Program for Brain Science, Field E from Ministry of Education, Culture, Sports and Technology, Japan. The research results were published online on 18, Jan 2012 in Brain.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of TDP-43 from the nucleus to the cytoplasm is considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type TDP-43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of ALS. We overexpressed wild-type human TDP-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 (Fig. A). They also showed regional cytoplasmic TDP-43 mislocalization with loss of nuclear TDP-43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles (Fig. B and C) and the Betz cell in the primary motor cortex (Fig. D), reminiscent of the spinal cord pathology of ALS patients. TDP-43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the TDP-43 mislocalization may lead to motoneuron degeneration. Furthermore, truncation of TDP-43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of TDP-43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed TDP-43 only in the nucleus of motoneurons. There is thus a species difference in TDP-43 pathology, and our monkey model recapitulates ALS pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis and developing therapy of sporadic ALS.

Takanori Yokota, MD, PhD
Department of Neurology and Neurological Science,
Tokyo Medical and Dental University
1-5-45 Yushima Bunkyo-ku, Toko 113-8519
Phone: +81-3-5803-5234
FAX: +81-3-5803-0169
email: tak-yokota.nuro(at)tmd.ac.jp
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