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

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disease. It primarily affects the motor neurons, leading to muscle weakness and eventual death of 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 that involves 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 the protein aggregation and slow growth in yeast cells. In the FUS, slow growth and protein aggregation is reduced with the chaperones CG32641 and CG6693, resulting in a lowering of the FUS toxicity. On the other hand, chaperones CG2911, CG2790, and CG8476 in the presence of TDP-43 overexpression, grow more slowly with increasing punctae in yeast cells. These chaperones increase the toxicity of TDP-43. Similarly, in FUS, Hsc20, CG7130, CG2911, and JdpC also showed a slow growth phenotype and increased protein aggregation in yeast cells. These chaperones enhance the toxicity of FUS.

This screening will enhance our understanding of ALS, and the chaperones identified in this study can serve as neuroprotective agents for ALS.