Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila.
Tauopathies, including Alzheimer's disease and fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of aberrantly phosphorylated-tau. Tau is a neuronal microtubule-associated protein involved in microtubule assembly and stabilization. Currently, the molecular mechanisms underlying tau-mediated cellular toxicity remain elusive. To address the determinants of tau neurotoxicity, we first characterized the cellular alterations resulting from the over-expression of a mutant form of human tau associated with FTDP-17 (tau V337M) in Drosophila. We found that the over-expression of tau V337M, in Drosophila larval motor neurons, induced disruption of the microtubular network at presynaptic nerve terminals and changes in neuromuscular junctions morphological features. Secondly, we performed a misexpression screen to identify genetic modifiers of the tau V337M-mediated rough eye phenotype. The screening of 1250 mutant Drosophila lines allowed us to identify several components of the cytoskeleton, and particularly from the actin network, as specific modifiers of tau V337M-induced neurodegeneration. Furthermore, we found that numerous tau modulators identified in our screen were involved in the maintenance of synaptic function. Taken together, these findings suggest that disruption of the microtubule network in presynaptic nerve terminals could constitute early events in the pathological process leading to synaptic dysfunction in tau V337M pathology.
Blard
Olivier
O
Inserm U614 (IFRMP), University of Rouen & Department of Genetics, Rouen University Hospital, Institute for Biomedical Research, Rouen, France.
Feuillette
Sébastien
S
Bou
Jacqueline
J
Chaumette
Boris
B
Frébourg
Thierry
T
Campion
Dominique
D
Lecourtois
Magalie
M
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000235:genetics; D018832:Molecular Chaperones / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000633:toxicity; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D014633:Valine / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*
D003598:Cytoskeletal Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D010455:Peptides; D016875:tau Proteins; C097188:polyglutamine; D008715:Methionine; D014633:Valine