Degenerative diseases result from cell decay caused by natural or external factors. A significant number of the population suffers from two specific degenerative diseases, Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Investigations have found that mutations in the TAR DNA binding protein (TDP-43), a transcriptional repressor which regulates the mRNA stability, transport and local translation in neurons, are linked to both ALS and FTD. Recent studies have shown that TDP-43 colocalizes with stress granules (SG), foci that form during stress conditions by the aggregation of proteins and RNAs. Our research group is focused on wild-type and human mutant TDP-43, fused with a fluorescent protein (mRuby) for imaging localization and expression in vivo to investigate the concentration gradients required for aggregation to occur. Driven by doxycycline-dependent transcription, preliminary results for wild-type of TDP-43 show clear aggregation with a concentration of 40 ng/uL of the doxycycline (DOX). The TDP-43 aggregates appear to be in the nucleus of the yeast cells, but further tests will be done to confirm this hypothesis. We will also test how the nutritional environment of the cell affects the aggregation by using different media. Human disease-linked mutants of TDP-43 (M337V and Q331K) are being constructed to test their aggregation rate and effects in yeast cells.

Concentration dependence of TDP-43 aggregation during stress conditions

255th National Meeting (2018)

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