The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Drug Discovery
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss.
• Currently, no effective treatments exist for ALS, highlighting the urgent need for therapeutic strategies.

Purpose of the Study:

• To identify existing drugs that can be repurposed for ALS treatment using a phenotypic drug screen.
• To investigate the potential of targeting the Src/c-Abl signaling pathway for ALS therapy.

Main Methods:

• Generated induced pluripotent stem cell (iPSC)-derived motor neurons from ALS patients with SOD1 mutations.
• Performed a phenotypic screen to identify compounds that enhance motor neuron survival.
• Utilized small interfering RNAs (siRNAs) to knockdown Src and c-Abl expression.
• Administered bosutinib to ALS patient-derived motor neurons and an ALS mouse model.

Main Results:

• Over half of the identified drug hits targeted the Src/c-Abl signaling pathway.
• Src/c-Abl inhibitors and knockdown significantly increased the survival of ALS iPSC-derived motor neurons.
• Bosutinib demonstrated efficacy by boosting autophagy, reducing misfolded SOD1 protein, and normalizing mitochondrial gene expression.
• Bosutinib improved survival in motor neurons from various ALS genetic subtypes and extended survival in an ALS mouse model.

Conclusions:

• The Src/c-Abl signaling pathway is a promising therapeutic target for amyotrophic lateral sclerosis.
• Drug repurposing, specifically targeting Src/c-Abl, offers a viable strategy for developing novel ALS treatments.
• Bosutinib shows potential as a therapeutic agent for ALS, warranting further investigation.