Drosophila model for TDP-43 proteinopathy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (7), p.3169-3174
• Main Authors: Li, Yan, Ray, Payal, Rao, Elizabeth J, Shi, Chen, Guo, Weirui, Chen, Xiaoping, Woodruff, Elvin A. III, Fushimi, Kazuo, Wu, Jane Y
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Animal models; Animals; Animals, Genetically Modified; Axons; Binding sites; Biological Sciences; Disease Models, Animal; DNA-Binding Proteins - metabolism; Drosophila; Gene expression; Humans; Insect morphology; Insects; Larvae; Luminescent Proteins - metabolism; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Motor neurons; Mushroom Bodies - metabolism; Neurological disorders; Neurons; Neurons - metabolism; Neurons - ultrastructure; Neurotoxicity; Pathology; Proteins; Red Fluorescent Protein; Retinal Degeneration - etiology; Retinal Degeneration - metabolism; Swelling; TDP-43 Proteinopathies - complications; TDP-43 Proteinopathies - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0913602107

Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.