Fly Model of Neurodegeneration Reveals Novel Suppressor Genes of TDP-43 Toxicity

Scientists have developed a new approach to study motor neuron degeneration by tracking single motor axons in the legs of adult Drosophila, allowing them to combine the power of fruit fly genetics with imaging age-related changes in synaptic and axonal morphology of motor neurons. Researchers led by Jemeen Sreedharan of the Babraham Institute in Cambridgeshire, UK, and Marc Freeman of University of Massachusetts Medical School in Worcester, MA, overexpressed the ALS-causing mutant protein, TDP-43Q331K, in the fly legs, and then conducted forward genetic screens to identify mutants with resistance to TDP-43-mediated neurodegeneration. As reported in August 17 Current Biology, the researchers identified three suppressor genes – hat-trick and xmas-2, and the known modifier of neurodegeneration, shaggy/GSK3 (see April 2013 news). Interestingly, these suppressors did not suppress Wallerian degeneration, suggesting that TDP-43 kills neurons via a distinct process. The researchers are currently validating these results in mammalian models.

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Sreedharan J, Neukomm LJ, Brown RH Jr, Freeman MR. Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. Curr Biol. 2015 Aug 17;25(16):2130-6.  Epub Jul 28. [Pubmed]


disease-als disease-ftd topic-preclinical
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