View Program - 63rd Annual Drosophila Research Conference

Trans active response (TAR) DNA-Binding protein 43 (TDP-43), an evolutionarily conserved RNA/DNA binding protein that regulates RNA processing, is known to form pathological, cytoplasmic inclusions in numerous neurodegenerative diseases. These cytoplasmic accumulations, collectively referred to as TDP-43 proteinopathy, are a hallmark of motor neuron degeneration in amyotrophic lateral sclerosis (ALS, 97% of cases) and are also detected in nearly half of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) cases, establishing TDP-43 as an important candidate for modeling neurodegenerative disease. Drosophila models of TDP-43 proteinopathy in ALS and other neurological disorders have elucidated important molecular dynamics of neurodegeneration, yet such models have not yet been employed to understand TDP-43 dependent pathomechanisms in dementia. Given the striking overlap between ALS and FTD and our own success in modeling TDP-43 proteinopathy in a fly model of ALS, we have developed a novel fruit fly model of dementia by overexpressing human TDP-43 in the mushroom bodies (MBs) of the Drosophila brain. Insect MBs form an elaborate, associative network that overlaps in function and gene expression with neurons in the human hippocampus and frontal cortex, making it an appropriate brain structure to model human dementia. We demonstrate that TDP-43 mislocalizes from the nucleus to the cytoplasm and forms axonal inclusions accompanied by age-dependent behavioral deficits and axonal degeneration in MBs. Importantly, cognitive deficits in working memory and sleep appear prior to our ability to detect axonal degeneration, paralleling what is seen in human disease. Based on recent studies identifying a role for TDP-43 in translation dysregulation, we sought to identify the molecular targets of TDP-43 in the MBs using RNA immunoprecipitations and RNAseq. These experiments identified several candidate targets of TDP-43 in mushroom bodies, including Dally-like protein (Dlp/GPC6), a translational target that we recently reported in Drosophila ALS models and patients. These findings suggest that TDP-43 overexpression in MBs causes FTD-relevant phenotypes that may help uncover novel mechanisms of disease. Future experiments are aimed at identifying additional FTD-relevant targets of TDP-43, including novel therapeutic strategies.

TDP-43 expression in dementia-relevant circuits causes axonal degeneration and behavioral deficits in Drosophila