Nuclear pore complex dysfunction drives TDP-43 pathology in ALS.

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration and TDP-43 aggregation.
• Impaired autophagy and protein misfolding are known ALS features.
• The nuclear pore complex (NPC) is increasingly recognized as a critical, redox-sensitive component in ALS.

Purpose of the Study:

• To investigate the role of NPC integrity in ALS pathogenesis.
• To determine if NPC dysfunction is linked to TDP-43 pathology and oxidative stress.
• To explore nucleocytoplasmic transport as a potential therapeutic target for ALS.

Main Methods:

• Analysis of postmortem spinal cord tissue from ALS patients and mouse models.
• CRISPR-mediated depletion of NPC components (NUP107) in human cells.
• TDP-43 knockdown experiments.
• Oxidative stress induction and assessment of NPC subunit carbonylation using oxime blotting and DNPH assays.

Main Results:

• Loss of NPC components (NUP107, NUP93, FG-repeat proteins) is a consistent finding in ALS models.
• NUP107 depletion induces ALS hallmarks: cytoplasmic TDP-43, increased phosphorylation, and autophagy defects.
• TDP-43 knockdown affects NPC composition, indicating a feedback loop.
• Oxidative stress worsens NPC mislocalization and TDP-43 aggregation.
• NPC FG-repeat subunits are directly carbonylated by oxidative stress, compromising NPC integrity.

Conclusions:

• NPC dysfunction is a redox-sensitive driver of TDP-43 pathology in ALS.
• Nucleocytoplasmic transport is a promising therapeutic avenue for ALS.
• Oxidative damage to NPC proteins provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration in ALS.