AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

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 di...

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Bibliographic Details
Published inBiophysical journal Vol. 116; no. 8; pp. 1380 - 1385
Main Authors March, Zachary M., Mack, Korrie L., Shorter, James
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 23.04.2019
The Biophysical Society
Subjects
Adenosine Triphosphatases - chemistry
Adenosine Triphosphatases - metabolism
alpha-Synuclein - metabolism
Animals
Biophysical
Caenorhabditis elegans
Disease Models, Animal
Heat-Shock Proteins - metabolism
Humans
Neurodegenerative Diseases - metabolism
Protein Conformation
Protein Folding
Protein Transport
Saccharomyces cerevisiae - metabolism
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Summary: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 (PANet) 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.
ISSN:0006-3495
1542-0086
DOI:10.1016/j.bpj.2019.03.007