Rac1 inhibition prevents axonal cytoskeleton dysfunction in transthyretin amyloid polyneuropathy.
Journal
Cell reports
Journal Volume
44
Journal Issue
10
Start Page
116411
ISSN
2211-1247
Date Issued
2025-10-28
Author(s)
Magalhães, Joana
Pacheco Dias, Vítor
Eira, Jessica
Oliveira da Silva, Marina I
Nóvoa, Guilherme
Martins, Margarida
Kan, Yu Yu
Dias, Andreia
Carvalho, Estefânia
Santos, Mariana
Seixas, Ana I
Coelho, Teresa
Taipa, Ricardo
Paes-de-Faria, Joana
Lemos, Carolina
Liz, Márcia A
Abstract
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.
Subjects
CP: Molecular biology
CP: Neuroscience
Rac1
axonal degeneration
genetic modifiers
neuronal cytoskeleton
peripheral neuropathy
transthyretin amyloidosis
SDGs
Type
journal article