The role of ER stress genes in modulating the toxicity of TDP43 in yeast ALS model

Parappuram, Irene Tomy and Patel, Basant Kumar (2019) The role of ER stress genes in modulating the toxicity of TDP43 in yeast ALS model. Masters thesis, Indian institute of technology Hyderabad.

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Abstract

TDP43 is an amyloid protein widely found in many neurodegenerative diseases. ALS or Amyotrophic Lateral Sclerosis is one such fatal disease, in which pathological TDP43 aggregates have been found in upto 97% of patients. The presence of misfolded proteins cause a condition n cell called as ER Stress, which activates Unfolded Protein Response (UPR). The transmembrane protein IRE1 is the major mediator in this pathway. IRE1 actvates HAC1 and this cascade leads o upregulation of genes that mitigate ER stress by refolding proteins; or in worst cases when rescue becomes impossible, helps undergo apoptosis. In this work, we have tried to elucidate the mechanism/pathway by which TDP43 causes toxicity and the possible roles of ER stress genes in mitigating this risk. Emphasis is on IRE1, as it is the initiator of UPR. Yeast is used as the model of ALS in this study, as TDP43 can form aggregates and also it is toxic.

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