AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

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. AAAþ (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 AAAþ 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 AAAþ translocases like Hsp104 and PAN will reveal promising agents to combat protein misfolding toxicity in neurodegenerative disease.

RNA-binding and prion domains: the Yin and Yang of phase separation

“…Nuclear polyadenylated RNA-binding protein 3 Nab3 and Transcriptional regulatory protein Gat1), chromosome organization (Tubulin gamma chain Tub4 and DNA repair and recombination protein Rad52), ribosome and mitochondrion (37S ribosomal protein Sws2 and 37S ribosomal protein S7 Rsm7), degradation and autophagy (Nuclear protein localization protein 4 Npl4, Autophagy-related protein 3 Atg3 and Ubiquitin ligase complex F-box protein Ufo1) and molecular chaperones (Heat shock protein homologue Sse2 and prion Cerevisin Prb1). We also detected HSP104, a disaggregase with valuable therapeutic application ( 70 , 71 ), able to resolve diverse protein aggregates in response to environmental stress. In particular, Hsp104 actively remodels amyloids and toxic soluble oligomers formed by several disease-linked proteins ( 72 , 73 ).…”

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

“…Because of the unfolding properties of VCP also other AAA+ proteins have been proposed as potent therapeutic agents, especially in solving protein misfolding and aggregation in neurodegenerative diseases. Although not functionally related to ERAD, the repurposing of two AAA+ proteins, including Hsp104 and proteasome-activating nucleotidase (PAN) were shown to protect from protein misfolding in several neurodegenerative animal models [159]. Furthermore, transgenic expression of PAN in rods of mice lacking the γ-subunit of transducin (G γ −/− ) resulted in increased photoreceptor survival accompanied by preserved visual function [132].…”

Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity

“…The remarkable ability of Hsp104 to dissolve prions is intriguing, as prions are commonly perceived as ineradicable. We have suggested that Hsp104 could be applied to eliminate aggregated species and toxic, soluble oligomers linked to neurodegeneration (March et al, 2019; Shorter, 2008). Indeed, Hsp104 actively remodels amyloids and toxic soluble oligomers formed by several disease-linked proteins (Castellano et al, 2015; DeSantis et al, 2012; Liu et al, 2011; Lo Bianco et al, 2008; Michalska et al, 2019; Park et al, 2017).…”