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Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation
Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation
Akihiro Sugai
(Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan)
Taisuke Kato
(Department of System Pathology for Neurological Disorders, Brain Science Branch, Center for Bioresource-based Research, Brain Research Institute, Niigata University, Niigata 951-8585, Japan)
Akihide Koyama
(Division of Legal Medicine, Graduate School of Medicine and Dental Science, Niigata University, Niigata 951-8585, Japan)
Yuka Koike
(Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan)
Takuya Konno
(Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan)
Tomohiko Ishihara
(Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Center for Bioresource-based Research, Brain Research Institute, Niigata University, Niigata 951-8585, Japan)
Osamu Onodera
(Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Corresponding author.)
Journal: Neurobiology of Disease
•
• Elsevier
• ISSN: 1095-953X
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.