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Purification of Hsp104, a Protein Disaggregase
Published on: September 30, 2011
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Artificial Hsp104-mediated systems for re-localizing protein aggregates
Arthur Fischbach1,2, Angela Johns3, Kara L Schneider3
1Institute for Biomedicine, Sahlgrenska Academy, Centre for Ageing and Health-AgeCap, University of Gothenburg, Gothenburg, Sweden. arthur.fischbach@age.mpg.de.
Nature Communications
|May 10, 2023
Summary
Spatial protein quality control (sPQC) can be manipulated to remove toxic protein aggregates, like mutant huntingtin, from cells. This study shows artificially targeting aggregates protects cells from death, offering new insights into neurodegenerative diseases and aging.
Area of Science:
- Cell Biology
- Neuroscience
- Aging Research
Background:
- Spatial protein quality control (sPQC) sequesters misfolded proteins into cellular inclusions to mitigate toxicity.
- The role of sPQC in cellular fitness, neurodegenerative diseases, and aging remains an active area of investigation.
- Huntington's disease is characterized by aggregates of mutant huntingtin (mHtt).
Purpose of the Study:
- To develop Hsp100-based systems for artificially targeting protein aggregates to non-canonical locations.
- To investigate the impact of spatial sequestration of protein aggregates on cellular fitness and survival.
- To explore the potential of this approach in studying neurodegenerative diseases and aging.
Main Methods:
- Construction of Hsp100-based systems in budding yeast.
- Artificial targeting of mutant huntingtin (mHtt) aggregates to daughter cells, eisosomes, and endosomes.
- Manipulation of endogenous age-associated misfolded protein inclusions.
- Application of the system in human cells.
Main Results:
- Artificial targeting of mHtt aggregates to daughter cells and organelles was achieved.
- Removal of mHtt inclusions from mother cells protected them from cell death, suggesting cytotoxicity.
- Sequestration of endogenous age-associated misfolded proteins did not significantly impact cell lifespan.
- The system demonstrated efficacy in manipulating mHtt inclusion formation in human cells.
Conclusions:
- Artificial spatial sequestration of toxic protein aggregates can protect cells from death.
- This approach provides a novel tool to study the cytotoxicity of protein aggregates in diseases like Huntington's.
- The Hsp100-based system offers a potential complementary method for investigating sPQC in aging and neurodegenerative conditions.
