Autophagic clearance of TDP-43 inclusions is mediated by a novel protein in FTLD-U

論文翻譯標題: 新穎蛋白在額顳葉退化症中參與自噬性清除TDP-43包含體的研究
  • 徐 唯恩

學生論文: Master's Thesis


Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease characterized by neuronal loss in frontal/temporal lobe of brain associated with cytoplasmic and nuclear inclusions resulting in patient’s behavior/language dysfunction and motor deficit TDP-43 has been identified as the major disease protein for FTLD with ubiquitin-positive inclusions (FTLD-U) Under pathological condition TDP-43 mislocalizes into cytoplasm and forms neurotoxic aggregations Autophagy is a self-degradative process in clearing misfolded or aggregated proteins In previous studies autophagy activators can alleviate the pathogenesis in FTLD-U mouse model and the novel protein represent in this thesis has beneficial effects in Alzheimer’s disease (AD) by preventing beta-amyloids to accumulate into the plaques Hence we intend to investigate whether this protein can provide neuroprotective effects in FTLD-U by modulating autophagic process for degrading TDP-43 inclusions First the dysregulation of the protein we focused in FTLD-U mice indicated this protein might play a role in FTLD-U pathology Second the interaction of the novel protein with autophagy-related protein ATF4 leaded to the hypothesis that it might involve in regulating autophagy The clearance of TDP-43 inclusions and the induction of autophagy by overexpressing this protein were both observed in FTLD-U cell model Therefore we generated a mouse model which forebrain-specifically overexpressed both TDP-43 and the protein of our interest Comparing with FTLD-U mouse autophagy was induced in this double transgenic mice resulting in the rescue of behavioral performances and the clearance of TDP-43 inclusions Taken together autophagy can be induced by this novel protein and take part in the clearance of TDP-43 inclusions thus it may be a therapeutic target in rescuing the pathological phenotype of FTLD-U
獎項日期2015 8月 27
監督員Kuen-Jer Tsai (Supervisor)