Rac1 inhibition prevents cytoskeleton dysfunction and axonal degeneration in Transthyretin Amyloid Polyneuropathy

Transthyretin Amyloid Polyneuropathy (ATTR-PN) is characterized by the deposition of amyloidogenic TTR particularly in dorsal root ganglia (DRG) and peripheral nerve axons leading to a sensory axonopathy. Here, we investigated the role of cytoskeleton alterations in peripheral axons from an ATTR-PN mouse model. We employed the knock-in hTTRA97S mouse model for ATTR-PN to examine cellular and molecular changes in peripheral axons. Our approach included proteomic analysis of the sural nerve, live imaging techniques, and pharmacological intervention targeting Rac1. Additionally, we used DNA samples gathered from individuals diagnosed with ATTR-PN, including early-onset and late-onset cases, to uncover genetic variants of cytoskeleton regulators related to distinct disease onsets.