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Updated: Jan 26, 2026
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Interview: Protein Folding and Studies of Neurodegenerative Diseases
Published on: July 16, 2008
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AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease
Zachary M March1, Korrie L Mack1, James Shorter1
1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Biophysical Journal
|April 7, 2019
Summary
Repurposing AAA+ protein translocases, like Hsp104 and PAN, shows promise for treating neurodegenerative diseases. These agents can break down toxic protein clumps, offering a new therapeutic strategy for protein misfolding disorders.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Neurodegenerative diseases are linked to protein misfolding and overwhelmed cellular protein quality control systems.
- Current treatments for these conditions are limited, highlighting the need for novel therapeutic strategies targeting toxic protein aggregates.
Purpose of the Study:
- To explore the potential of repurposing AAA+ (ATPases associated with diverse cellular activities) protein translocases as therapeutic agents for neurodegenerative diseases.
- To evaluate the efficacy of Hsp104 and proteasome-activating nucleotidase (PAN) in disassembling toxic protein conformers and mitigating disease pathology.
Main Methods:
- Reviewing existing research on Hsp104 and its protective effects in animal models of neurodegeneration.
- Assessing the impact of enhanced Hsp104 variants on protein misfolding toxicity in various model organisms (yeast, C. elegans, mammalian cells).
- Examining the effectiveness of an engineered PAN variant (PANet) in a mouse model of protein misfolding-induced retinopathy.
Main Results:
- Hsp104 demonstrated significant protection against neurodegeneration in multiple animal models.
- Enhanced Hsp104 variants effectively reduced protein misfolding toxicity in yeast, C. elegans, and mammalian cells.
- The engineered PAN variant (PANet) successfully mitigated photoreceptor degeneration in a mouse model of retinopathy.
Conclusions:
- AAA+ protein translocases, specifically Hsp104 and PAN, represent a promising therapeutic avenue for combating protein misfolding toxicity in neurodegenerative diseases.
- Further investigation and engineering of these translocases could lead to the development of potent agents for treating a range of protein misfolding disorders.
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