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 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.