Abstract
Protein misfolding and overloaded proteostasis networks underlie a range of neurodegenerative diseases. No cures exist for these diseases, but developing effective therapeutic agents targeting the toxic, misfolded protein species in disease is one promising strategy. AAA+ (ATPases associated with diverse cellular activities) protein translocases, which naturally unfold and translocate substrate proteins, could be potent therapeutic agents to disassemble toxic protein conformers in neurodegenerative disease. Here, we discuss repurposing AAA+ protein translocases Hsp104 and proteasome-activating nucleotidase (PAN) to alleviate the toxicity from protein misfolding in neurodegenerative disease. Hsp104 effectively protects various animal models from neurodegeneration underpinned by protein misfolding, and enhanced Hsp104 variants strongly counter neurodegenerative disease-associated protein misfolding toxicity in yeast, Caenorhabditis elegans, and mammalian cells. Similarly, a recently engineered PAN variant (PAN(et)) mitigates photoreceptor degeneration instigated by protein misfolding in a mouse model of retinopathy. Further study and engineering of AAA+ translocases like Hsp104 and PAN will reveal promising agents to combat protein misfolding toxicity in neurodegenerative disease.