Related Experiment Video
Updated: May 14, 2026
Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice
Published on: February 24, 2026
Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant
Marcelo R Vargas1, Neal C Burton, Jennifer Kutzke
1Division of Pharmaceutical Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.
Abstract:
The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1(G93A) mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) activation may impact amyotrophic lateral sclerosis (ALS). While Nrf2 absence showed no harm, targeted Nrf2 overexpression in neurons or muscle delayed ALS onset but did not improve survival in mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates antioxidant and detoxification enzymes, offering cellular protection.
- Amyotrophic lateral sclerosis (ALS) is linked to mutations in Cu/Zn-superoxide dismutase (SOD1), leading to motor neuron loss.
- Previous studies indicated Nrf2 activation in astrocytes could delay neurodegeneration in ALS models.
Purpose of the Study:
- To investigate the role of Nrf2 in ALS pathogenesis.
- To determine the effects of Nrf2 absence or cell-specific overexpression on disease progression and survival in mouse models of ALS.
Main Methods:
- Utilized mutant human SOD1 (hSOD1) expressing mice to model ALS.
- Assessed the impact of Nrf2 gene knockout on disease parameters.
- Examined the effects of restricted Nrf2 overexpression in neurons and type II skeletal muscle fibers.
Main Results:
- Absence of Nrf2 did not detrimentally affect disease onset or survival in two different hSOD1 ALS mouse models.
- Restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset in hSOD1(G93A) mice.
- Nrf2 overexpression in these specific cell types failed to extend the survival of hSOD1(G93A) mice.
Conclusions:
- The absence of Nrf2 does not appear to worsen ALS progression in these models.
- Targeting Nrf2 in specific cell types like neurons or skeletal muscle may influence disease onset but not overall survival.
- Therapeutic strategies involving Nrf2 for ALS should consider both the target molecule and the specific cell types involved.
