Rac1 inhibition prevents axonal cytoskeleton dysfunction in transthyretin amyloid polyneuropathy.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic transthyretin, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knockin mice. Proteomics of hTTRA97S sural nerves revealed dysregulation of actin-related proteins. hTTRA97S DRG neurons presented a defective actin distribution in growth cones along with a reduction in axonal actin trails, impacting synaptic vesicle recycling. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation. Importantly, Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. In late-onset ATTRv-PN patients, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonopathy in ATTRv-PN and highlight Rac1 as a promising therapeutic target.