HSPA1A and neurodegenerative disease: 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.