A Drosophila model for TDP-43 proteinopathy.
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.
Li
Yan
Y
Department of Neurology, Lurie Cancer Center, Center for Genetic Medicine, Northwestern University School of Medicine, Chicago, IL 60611, USA. l-yan@northwestern.edu
Ray
Payal
P
Rao
Elizabeth J
EJ
Shi
Chen
C
Guo
Weirui
W
Chen
Xiaoping
X
Woodruff
Elvin A
EA
Fushimi
Kazuo
K
Wu
Jane Y
JY
D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D024521:Mushroom Bodies / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism*; D057177:TDP-43 Proteinopathies / Q000150:complications / Q000378:metabolism*; D000097573:Red Fluorescent Protein
D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein