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@ARTICLE{Butzlaff:836327,
      author       = {Butzlaff, Malte and Hannan, Shabab B. and Karsten, Peter
                      and Lenz, Sarah and Ng, Josephine and Voßfeldt, Hannes and
                      Prüßing, Katja and Pflanz, Ralf and Schulz, Jörg B. and
                      Rasse, Tobias and Voigt, Aaron},
      title        = {{I}mpaired retrograde transport by the {D}ynein/{D}ynactin
                      complex contributes to {T}au-induced toxicity},
      journal      = {Human molecular genetics},
      volume       = {24},
      number       = {13},
      issn         = {1460-2083},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2017-05448},
      pages        = {3623 - 3637},
      year         = {2015},
      abstract     = {The gene mapt codes for the microtubule-associated protein
                      Tau. The R406W amino acid substitution in Tau is associated
                      with frontotemporal dementia with parkinsonism linked to
                      chromosome 17 (FTDP-17) characterized by Tau-positive
                      filamentous inclusions. These filamentous Tau inclusions are
                      present in a group of neurodegenerative diseases known as
                      tauopathies, including Alzheimer's disease (AD). To gain
                      more insights into the pathomechanism of tauopathies, we
                      performed an RNAi-based large-scale screen in Drosophila
                      melanogaster to identify genetic modifiers of
                      Tau[R406W]-induced toxicity. A collection of RNAi lines,
                      putatively silencing more than 7000 genes, was screened for
                      the ability to modify Tau[R406W]-induced toxicity in vivo.
                      This collection covered more than $50\%$ of all protein
                      coding fly genes and more than $90\%$ of all fly genes known
                      to have a human ortholog. Hereby, we identified 62 genes
                      that, when silenced by RNAi, modified Tau-induced toxicity
                      specifically. Among these 62 modifiers were three subunits
                      of the Dynein/Dynactin complex. Analysis on segmental nerves
                      of fly larvae showed that pan neural Tau[R406W] expression
                      and concomitant silencing of Dynein/Dynactin complex members
                      synergistically caused strong pathological changes within
                      the axonal compartment, but only minor changes at synapses.
                      At the larval stage, these alterations did not cause
                      locomotion deficits, but became evident in adult flies. Our
                      data suggest that Tau-induced detrimental effects most
                      likely originate from axonal rather than synaptic
                      dysfunction and that impaired retrograde transport
                      intensifies detrimental effects of Tau in axons. In
                      conclusion, our findings contribute to the elucidation of
                      disease mechanisms in tauopathies like FTDP-17 or AD.},
      cin          = {INM-11},
      ddc          = {570},
      cid          = {I:(DE-Juel1)INM-11-20170113},
      pnm          = {572 - (Dys-)function and Plasticity (POF3-572)},
      pid          = {G:(DE-HGF)POF3-572},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000357523900003},
      pubmed       = {pmid:25794683},
      doi          = {10.1093/hmg/ddv107},
      url          = {https://juser.fz-juelich.de/record/836327},
}