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

TY - JOUR

T1 - Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioral phenotypes that characterize ALS and FTLD

AU - Diaper, Danielle C.

AU - Adachi, Yoshitsugu

AU - Lazarou, Luke

AU - Greenstein, Max

AU - Simoes, Fabio A

AU - Di Domenico, Angelique

AU - Solomon, Daniel A.

AU - Lowe, Simon

AU - Alsubaie, Rawan

AU - Cheng, Daryl

AU - Buckley, Stephen

AU - Humphrey, Dickon M

AU - Shaw, Christopher E

AU - Hirth, Frank

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddt243

DO - 10.1093/hmg/ddt243

M3 - Article

C2 - 23727833

SN - 1460-2083

VL - 22

SP - 3883

EP - 3893

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

ER -