ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Mutations in copper/zinc-superoxide dismutase (SOD1) are a known cause of familial amyotrophic lateral sclerosis (ALS).
• The precise molecular mechanisms underlying SOD1-induced motor neuron death remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular pathway linking mutant SOD1 (SOD1(mut)) to motor neuron death in familial ALS.
• To investigate the role of endoplasmic reticulum (ER)-associated degradation (ERAD) and the ASK1 pathway in SOD1(mut)-induced neurotoxicity.

Main Methods:

• Investigated the interaction between SOD1(mut) and Derlin-1, a key component of the ERAD machinery.
• Assessed ER stress markers and activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway in response to SOD1(mut).
• Utilized Derlin-1-derived oligopeptides to disrupt SOD1(mut)-Derlin-1 binding and employed ASK1 knockout models in SOD1(mut) transgenic mice.

Main Results:

• SOD1(mut) specifically interacts with Derlin-1, leading to ERAD dysfunction and subsequent ER stress.
• ER stress activates the ASK1-dependent cell death pathway, contributing to motor neuron demise.
• Disrupting the SOD1(mut)-Derlin-1 interaction or inhibiting ASK1 significantly reduced ER stress, ASK1 activation, and motor neuron loss, extending lifespan in mouse models.

Conclusions:

• The interaction between SOD1(mut) and Derlin-1 triggers ER stress and activates the ASK1 pathway, which is critical for familial ALS pathogenesis.
• Targeting the SOD1(mut)-Derlin-1 interaction or the ASK1 pathway represents a potential therapeutic strategy for familial ALS.