title: Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that are characterized by cytoplasmic aggregates and nuclear clearance of TAR DNA-binding protein 43 (TDP-43). Studies in Drosophila, zebrafish and mouse demonstrate that the 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 homologue (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 behavioural 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 Excitatory amino acid transporter 1 (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 behavioural phenotypes in Drosophila that also characterize ALS and FTLD and identify the glutamate transporters 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.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Diaper
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Adachi
authors.forename: Luke
authors.initials: L
authors.lastname: Lazarou
authors.forename: Max
authors.initials: M
authors.lastname: Greenstein
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Simoes
authors.forename: Angelique
authors.initials: A
authors.lastname: Di Domenico
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Solomon
authors.forename: Simon
authors.initials: S
authors.lastname: Lowe
authors.forename: Rawan
authors.initials: R
authors.lastname: Alsubaie
authors.forename: Daryl
authors.initials: D
authors.lastname: Cheng
authors.forename: Stephen
authors.initials: S
authors.lastname: Buckley
authors.forename: Dickon M
authors.initials: DM
authors.lastname: Humphrey
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Frank
authors.initials: F
authors.lastname: Hirth
mesh_terms: D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007814:Larva; D051379:Mice; D009043:Motor Activity; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C421004:Eaat2 protein, Drosophila; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2