Regional Cytoplasmic TDP-43 Mislocalization Is Recapitulated in Non-Human Primate Mimicking ALS (IN9-1.002)

Abstract

Objective: To investigate the pathological role of wild-type TDP-43, we develop non-human primate model of sporadic amyotrophic lateral sclerosis patients (ALS). Background ALS is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of TDP-43 from the nucleus to the cytoplasm and the presence of cystatin C–positive Bunina bodies are considered pathological hallmarks of ALS, but their significance has not been fully elucidated. All reported rodent transgenic models of ALS using wild-type TDP-43 failed to recapitulate these features. Design/Methods: To investigate the pathological role of wild-type TDP-43, we over-expressed Flag tagged human wild-type TDP-43 in spinal motoneurons in 10 non-human primate, cynomolgus monkey by directly injecting adeno-associated virus (AAV) 1 vector to the 6th cervical cord. Results: These monkeys developed progressive motor weakness and muscle atrophy with fasciculation first in distal hand muscles. Despite the diffuse expression of exogenous TDP-43 in the spinal cord, TDP-43 mislocalization and neuron loss predominantly occurred in the lateral nuclear group in Rexed lamina IX, in which large neurons are mostly alpha-motoneurons, reminiscent of the spinal cord pathology of ALS. TDP-43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. cystatin Spinal motoneuron sometimes showed C–positive cytoplasmic aggregates. Intersetingly, immnostaining with an anti-Flag antibody identified its nuclear or cytoplasmic immunoreactivity in some Betz cells in precentral gyrus restricted to the forelimb area contralateral to the injection. Conclusions: These findings suggest that cytoplasmic TDP-43 mislocalization leads to alpha-motoneuron degeneration. The tropism of TDP-43 mislocalization in the monkey spinal cord and motor cortex is similar to the ALS pathology. Our monkey model is expected to be a powerful tool for investigating pathogenesis of sporadic ALS and mechanism of its propagation. Disclosure: Dr. Yokota has nothing to disclose. Dr. Sasaguri has nothing to disclose. Dr. Ohkubo has nothing to disclose. Dr. Mizusawa has received personal compensation for activities with Tanabemitsubishi Co and Sanofi-Aventis Co. Dr. Mizusawa has received personal compensation in an editorial capacity for No to Shinkei and Clinical Neuroscience.