Oxidized SOD1 accelerates cellular senescence in neural stem cells
Teng Guan1, Ying Guo1,2, Ting Zhou1,3
1Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada.
Stem Cell Research & Therapy
|February 28, 2024
Summary
Oxidized human SOD1 (hSOD1) directly causes neural stem cell (NSC) senescence. Removing oxidized hSOD1 rejuvenates NSCs and improves extracellular vesicle quality, offering a therapeutic strategy.
Area of Science:
- Stem cell biology
- Neuroscience
- Oxidative stress research
Background:
- Neural stem cells (NSCs) undergo senescence, characterized by proliferation arrest and loss of stemness.
- Oxidative stress is implicated in NSC senescence, but a direct causal link remains unestablished.
- Oxidized human SOD1 (hSOD1) is toxic and linked to neurodegenerative diseases.
Purpose of the Study:
- To investigate the causal role of oxidized hSOD1 in NSC senescence.
- To determine if oxidized hSOD1 in extracellular vesicles (EVs) affects NSC aging and neuronal health.
Main Methods:
- Cultured NSCs from transgenic mice expressing hSOD1.
- Isolated extracellular vesicles (EVs) at various passages.
- Utilized a novel peptide-directed chaperone-mediated protein degradation system (CT4) to selectively remove oxidized SOD1.
Main Results:
- Oxidized hSOD1 increased in NSCs with passage, correlating with senescence biomarkers (P53, SA-β-Gal, HMGB1).
- Removal of oxidized hSOD1 restored NSC proliferation and stemness.
- EVs from senescent NSCs contained oxidized hSOD1, accelerating senescence in young NSCs and causing neuronal death; removal of oxidized hSOD1 abolished these effects.
Conclusions:
- Oxidized hSOD1 is a direct cause of NSC cellular senescence.
- Removing oxidized hSOD1 can rejuvenate NSCs and enhance the quality of derived EVs.
- Targeting oxidized hSOD1 presents a therapeutic avenue for age-related NSC decline and neurodegeneration.
