Rac1 inhibition prevents axonal cytoskeleton dysfunction in transthyretin amyloid polyneuropathy

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) involves amyloid deposition in nerves, causing sensorimotor axonopathy.
• The precise molecular mechanisms driving axonal degeneration in ATTRv-PN remain incompletely understood.

Purpose of the Study:

• To investigate cytoskeleton alterations in peripheral axons of an ATTRv-PN mouse model.
• To identify molecular pathways involved in cytoskeletal defects and axonal degeneration.
• To evaluate Rac1 as a potential therapeutic target.

Main Methods:

• Proteomic analysis of sural nerves from hTTRA97S knockin mice (ATTRv-PN model).
• Assessment of actin distribution and microtubule dynamics in dorsal root ganglia (DRG) neurons.
• Evaluation of axonal transport and synaptic vesicle recycling.
• Pharmacological inhibition of Rac1 activity.

Main Results:

• Proteomics revealed dysregulation of actin-related proteins in hTTRA97S mice.
• ATTRv-PN neurons exhibited defective actin distribution, reduced axonal actin trails, and impaired synaptic vesicle recycling.
• Microtubule dynamics and axonal transport were abnormal in mutant axons.
• Cytoskeletal defects preceded axonal degeneration and were mediated by Rac1 hyperactivation.
• Rac1 inhibition rescued cytoskeletal alterations and prevented axonal degeneration.
• A RACGAP1 variant in patients supported the neuroprotective role of Rac1 inhibition.

Conclusions:

• Cytoskeletal defects are early events preceding axonopathy in ATTRv-PN.
• Rac1 hyperactivation plays a critical role in mediating these cytoskeletal defects.
• Rac1 inhibition represents a promising therapeutic strategy for ATTRv-PN.