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Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioral phenotypes that characterize ALS and FTLD

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Danielle C. Diaper, Yoshitsugu Adachi, Luke Lazarou, Max Greenstein, Fabio A Simoes, Angelique Di Domenico, Daniel A. Solomon, Simon Lowe, Rawan Alsubaie, Daryl Cheng, Stephen Buckley, Dickon M Humphrey, Christopher E Shaw, Frank Hirth

Original languageEnglish
Pages (from-to)3883-3893
Number of pages11
JournalHuman Molecular Genetics
Issue number19
Published1 Oct 2013

King's Authors


Amyotrophic Lateral Sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that are characterized by cytoplasmic aggregates and nuclear clearance of TDP-43. Studies in Drosophila, zebrafish and mouse demonstrate that neuronal dysfunction of TDP-43 is causally related to disease formation. However, TDP-43 aggregates are also observed in glia and muscle cells, which are equally affected in ALS and FTLD, yet it is unclear whether glia or muscle-specific dysfunction of TDP-43 contributes to pathogenesis. Here we show that similar to its human homologue, Drosophila TDP-43, Tar DNA binding protein homolog (TBPH), is expressed in glia and muscle cells. Muscle-specific knockdown of TBPH causes age-related motor abnormalities, whereas muscle-specific gain of function leads to sarcoplasmic aggregates and nuclear TBPH depletion, which is accompanied by behavioral deficits and premature lethality. TBPH dysfunction in glia cells causes age-related motor deficits and premature lethality. In addition, both loss and gain of Drosophila TDP-43 alter mRNA expression levels of the glutamate transporters EAAT1 and EAAT2. Taken together, our results demonstrate that both loss and gain of TDP-43 function in muscle and glial cells can lead to cytological and behavioral phenotypes in Drosophila that also characterize ALS and FTLD, and identify the glutamate transporter EAAT1/2 as potential direct targets of TDP-43 function. These findings suggest that together with neuronal pathology, glial- and muscle-specific TDP-43 dysfunction may directly contribute to the aetiology and progression of TDP-43-related ALS and FTLD.

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