Retrotransposon Activation Contributes to non-cell autonomous Neurodegeneration in a Drosophila TDP-43 Model of ALS.

− この都医学研セミナーは終了しました。 −

演者 Josh Dubnau
Dept of Anesthesiology Dept of Neurobiology and Behavior Stony Brook University(Professor)
会場 東京都医学総合研究所 2BC会議室
日時 平成30年3月8日(木)11:00~
世話人 齊藤 実 (学習記憶プロジェクトリーダー)
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TDP-43 is an aggregation-prone RNA and DNA binding protein that forms abnormal cytoplasmic inclusions in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD. The cascade of events leading aggregation, and the downstream outcomes that lead to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. Using an in vivo sensor, we find that such expression of hTDP-43 impairs the ability of siRNAs to silence their targets, and this impairment is exacerbated with advancing organismal age. The siRNA system is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. Using RNA sequencing, we also find that the loss of siRNA efficacy is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in glia vs neurons. One of the elements that is selectively active in response to glial expression of hTDP-43 is the endogenous retrovirus (ERV) gypsy. In fact, gypsy causally contributes to the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. The toxicity of TDP-43 appears to involve activation of DNA damage-mediated programmed cell death both in neurons and in glial cells, consistent with RTE-mediated effects in both cell types. Using in vivo imaging, we also establish that TDP-43 toxicity in glial cells involves a fundamental non-cell autonomous mechanism leading to programmed cell death of both glial cells, and adjacent neurons. Both the cell autonomous and non-cell autonomous effects appear to be mediated at least in part by gypsy expression initiated in glial cells. Like HERV-K, which is expressed in cortex of some ALS subjects, the Drosophila gypsy element retains a functional Env gene, which provides the conceptual potential for non-cell autonomous transfer of viral genetic material. We investigated this possibility in S2 cell co-culture experiments, and find that gypsy elements are indeed able to transfer reporter expression. Together, these findings are evocative of the known non-cell autonomous toxicity of astrocytes onto motor neurons in ALS. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD, and formally raise the possibility that ERV-mediated movement between cells could contribute to the focal onset and spread of neurodegenerative disorders within the nervous system.