The Foundational Concept: The nuclear pore is the cell's customs checkpoint regulating all traffic between nucleus and cytoplasm. C9orf72 dipeptide repeats gum up this portal, stranding critical proteins on the wrong side.

The Mechanism:

Mutation Source: The C9orf72 hexanucleotide repeat expansion (GGGGCC) is transcribed in both directions. Through repeat-associated non-ATG translation, this produces five dipeptide repeat proteins poly-GA, poly-GR, poly-PR, poly-PA, poly-GP.

Pore Targeting: Arginine-rich dipeptides (poly-GR, poly-PR) are particularly toxic. Their positive charge binds directly to phenylalanine-glycine (FG) repeats within nuclear pore complex proteins the hydrophobic mesh controlling transport.

Phase Separation: Dipeptides undergo liquid-liquid phase separation with FG-nucleoporins, forming hydrogel-like plugs within the central channel. This transforms dynamic pores into solid barriers.

Traffic Jam: Nuclear import receptors (importins, karyopherins) cannot traverse blocked pores. Transcription factors (CREB, NF-��B), RNA-binding proteins (TDP-43, FUS), and repair enzymes remain trapped in cytoplasm.

Nuclear Starvation: Nuclei lose essential proteins. mRNA export also fails transcripts accumulate in nucleus, unable to reach ribosomes. Cells cannot respond to stress or maintain homeostasis.

TDP-43 Mislocalization: TDP-43 normally shuttles between nucleus (gene regulation) and cytoplasm. Blocked import strands TDP-43 in cytoplasm, where it aggregates into toxic inclusions the hallmark pathology of ALS/FTD.

The Specificity:

Poly-GR and poly-PR show greatest toxicity in models

Toxicity correlates with nuclear pore binding affinity

Nucleoporin expression declines with age, compounding vulnerability

Therapeutic Implications:

Transport receptor upregulation (importin-��, transportin-1) competing for pore access

Dipeptide sequestration antibodies neutralizing before pore entry

Nuclear pore stabilizers preventing FG-nucleoporin phase separation

Antisense oligonucleotides reducing repeat transcription

This reframes C9orf72 ALS/FTD as nucleocytoplasmic transportopathy cellular communication failure at the nuclear envelope.