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Updated: Jul 19, 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
Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice
Susanne Petri1, Mahmoud Kiaei, Elizabeth Wille
1Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA. petri.susanne@mh-hannover.de
Abstract:
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.
Insights
Amyotrophic lateral sclerosis (ALS) motor neuron death is linked to Fas-induced apoptosis. Reducing Fas signaling in ALS mice modestly extended survival and preserved motor neurons, suggesting Fas pathway relevance in ALS.
Area of Science:
- Neuroscience
- Neurodegenerative Diseases
- Motor Neuron Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure.
- The exact molecular causes of motor neuron degeneration in ALS remain unclear.
- A motor neuron-specific apoptosis pathway involving Fas and nitric oxide (NO) has been identified.
- Motor neurons in ALS mouse models exhibit heightened sensitivity to Fas-induced cell death.
Purpose of the Study:
- To investigate the therapeutic potential of reducing Fas signaling in ALS.
- To determine if inhibiting the Fas pathway can ameliorate motor neuron degeneration and prolong survival in a mouse model of ALS.
Main Methods:
- Crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice.
- Assessed the impact of homozygous FasL mutation on motor neuron survival and overall survival in ALS mice.
Main Results:
- Mice with both G93A-SOD1 mutation and homozygous FasL mutation showed a statistically significant, albeit modest, extension in lifespan.
- A reduction in motor neuron loss was observed in these double-mutant mice.
- These findings suggest that blocking Fas signaling can offer neuroprotective benefits.
Conclusions:
- Motor neuron apoptosis mediated by the Fas pathway plays a significant role in the pathogenesis of ALS.
- Targeting the Fas pathway represents a potential therapeutic strategy for ALS treatment.
- Further research into Fas-mediated apoptosis in ALS is warranted.
