TY - JOUR
T1 - A Drosophila model for TDP-43 proteinopathy
AU - Li, Yan
AU - Ray, Payal
AU - Rao, Elizabeth J.
AU - Shi, Chen
AU - Guo, Weirui
AU - Chen, Xiaoping
AU - Woodruff, Elvin A.
AU - Fushimi, Kazuo
AU - Wu, Jane Y.
PY - 2010/2/16
Y1 - 2010/2/16
N2 - 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 testwhether increasedexpressionofwide- typehuman TDP-43(hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressinghTDP-43invariousneuronalsubpopulations. Expressionin 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 inmushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expressioninmotor neurons led to axon swelling, reductionin axonbranches andbouton numbers, andmotor 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 expressionis sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43may contribute to the pathogenesis of TDP-43 proteinopathy.
AB - 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 testwhether increasedexpressionofwide- typehuman TDP-43(hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressinghTDP-43invariousneuronalsubpopulations. Expressionin 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 inmushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expressioninmotor neurons led to axon swelling, reductionin axonbranches andbouton numbers, andmotor 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 expressionis sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43may contribute to the pathogenesis of TDP-43 proteinopathy.
KW - Amyotrophic lateral sclerosis
KW - Animal model
KW - RNA binding protein
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U2 - 10.1073/pnas.0913602107
DO - 10.1073/pnas.0913602107
M3 - Article
C2 - 20133767
AN - SCOPUS:77649258646
SN - 0027-8424
VL - 107
SP - 3169
EP - 3174
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -