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

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

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62 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)3883-3893
Number of pages11
JournalHuman Molecular Genetics
Issue number19
Publication statusPublished - 1 Oct 2013


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