However, WT Hsp104 is too tightly regulated and is unable to overcome widespread aggregation by neurodegenerative disease proteins such as TDP-43, FUS, and α-synuclein in yeast.29,30,63,64 Thus, we hypothesize that potentiated Hsp104 variants with reduced unfoldase activity for soluble proteins, and partial independence from Hsp70 may reside in an advantageous therapeutic window. This evidence concerns the gene TARDBP and neurodegenerative disease.