Overexpression of DnaJ chaperones in ameliorating toxicities associated with FUS and TDP-43

Abstract

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disease. It primarily affects the motor neurons, leading to muscle weakness and eventually death of the patients. Various factors, such as genetics, environment, age, etc, are involved in the etiopathogenesis of ALS. As ALS is a highly challenging and complex disease involving various pathogeneses linked with progressive motor neuron degeneration, it is difficult to have a single therapeutic target against this disease. ALS mutants of TDP-43 and FUS are showing slow growth as well as protein aggregation in the cytoplasm in yeast. Our study involves cloning of 38 Drosophila DnaJ domain chaperones and overexpressing them in a yeast ALS model. After the interaction of mutants TDP-43 and FUS with the DnaJ domain chaperones, they were categorized into suppressors and enhancers. The major hits on our screen were CG7872, Hsc70-4, and Mrj, which rescued TDP-43 toxicity by reducing protein aggregation and slow growth in yeast cells. In FUS, slow growth and protein aggregation are reduced with the chaperones CG32641 and CG6693, resulting in a lowering of FUS toxicity. On the other hand, chaperones CG2911, CG2790, and CG8476 in presence of TDP-43 overexpression, grows slower with an increase in the number of aggregates in yeast cells. These chaperones increase the toxicity of TDP-43. Similarly, in FUS, Hsc20, CG7130, CG2911, and JdpC also showed slow growth phenotype and an increase in protein aggregation in yeast cells. These chaperones enhance the toxicity of FUS. This screening will enhance our understanding of the ALS pathology, and the chaperones identified in this study can serve as neuroprotective agents for ALS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/656528v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16ed84dorg.highwire.dtl.DTLVardef@3ad413org.highwire.dtl.DTLVardef@39431borg.highwire.dtl.DTLVardef@164ae09_HPS_FORMAT_FIGEXP M_FIG C_FIG