Blocking Rac1 protein may prevent nerve damage in hATTR-PN: Lab study
Protein's overactivation may drive early nerve degeneration in patients
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Overactivation of Rac1, a protein that regulates components of a cell’s skeleton, may drive early nerve damage in hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), according to new data from a preclinical study.
The research team found that reducing Rac1 activity restored nerve cell structure and prevented nerve degeneration in an hATTR-PN mouse model. Further, in analyzing patient data, the team discovered that individuals carrying a specific mutation that ultimately suppresses Rac1 activity have a delayed symptom onset.
Altogether, per the team, these findings support Rac1 suppression as a potential new treatment strategy to slow or prevent nerve damage in people with hATTR-PN.
“Our findings … highlight Rac1 as a promising therapeutic target,” the researchers wrote.
The study, “Rac1 inhibition prevents axonal cytoskeleton dysfunction in transthyretin amyloid polyneuropathy,” was published in the journal Cell Reports.
hATTR-PN is caused by mutations in the TTR gene, which lead to the buildup of toxic clumps — called amyloid deposits — of the transthyretin protein. This mainly occurs in peripheral nerves, which relay sensory and motor information from the brain and spinal cord to the rest of the body, including to the legs and arms.
As a result, people with hATTR-PN, also known as familial amyloid polyneuropathy, experience symptoms such as progressive sensory loss, pain, and weakness that typically begin in the feet and hands.
Early-onset cases — occurring in people younger than age 50 — are marked by damage to nerve fibers, or axons, in small peripheral nerve fibers. Meanwhile, late-onset cases, involving individuals older than 50, “involve both small and large fiber damage with loss of all sensory modalities, despite less amyloid deposition relative to the severity of nerve fiber loss,” the researchers wrote.
According to the researchers, “these observations suggest the existence of mechanisms other than direct damage caused by amyloid fibers.”
New research focused on skeletal abnormalities in hATTR-PN
Previous studies have reported disruptions in the cytoskeleton, the cell’s structural framework, in people with several neurodegenerative diseases. Now, a team led by researchers in Portugal evaluated the potential role of cytoskeleton abnormalities in hATTR-PN-related axon degeneration.
The goal was to determine whether targeting specific pathways that modulate the cytoskeleton could help prevent nerve damage and offer a new therapeutic strategy for hATTR-PN.
The team first conducted analyses in a mouse model of hATTR-PN, called hTTRA97S, and in healthy mice (used as controls) at 9 months, before signs of axonal degeneration and symptoms are detected in the hTTRA97S mice.
A comprehensive protein analysis of the sural nerve, a sensory nerve in the lower leg, identified 245 proteins with significantly different levels between hTTRA97S and control mice. Several of the proteins showing higher levels in the mouse model were related to the cytoskeleton.
Experiments on lab-grown dorsal root ganglions (DRGs), a cluster of specialized sensory neurons, revealed clear abnormalities in the organization of actin, a key cytoskeletal component, in hTTRA97S mice. Actin filaments help maintain axonal structure and support the transport of important cargo within axons, which is key for nerve cell communication.
Specifically, DRGs from hTTRA97S mice showed disrupted actin networks in growth cones — the dynamic structures at the tips of axons that are essential for axon growth, maintenance, and repair. These growth cones were more likely to collapse, an early sign of axonal degeneration.
hTTRA97S DRG axons also showed fewer actin trails, which facilitate transport of actin filaments across the axon, and defects in recycling of synaptic vesicles, the small sacs that carry chemical signals to communicate with other nerve cells.
The researchers also examined microtubules, a major cytoskeletal component that transports essential cargo along axons. While the overall number of microtubules was not reduced in hTTRA97S sural nerves, their dynamics were abnormal, impairing axonal transport.
Specifically, mitochondria, which serve as a cell’s powerhouses, moved more slowly and less efficiently along axons in hTTRA97S sural nerves relative to controls. Transport of synaptic vesicles was also disrupted, suggesting that nerve cells were already functionally compromised at this early stage of the disease.
Given that all of these abnormalities occurred before axons began to degenerate or mice developed sensory symptoms, cytoskeletal dysfunction appears to be an early driver of axonal damage in hATTR-PN, rather than a consequence of amyloid buildup alone, the researchers concluded.
Scientists say targeting Rac1 may lead to less neurodegeneration
Further experiments identified Rac1, a protein that regulates cytoskeletal dynamics, as a key contributor to these early changes. Rac1 activity was abnormally increased in hTTRA97S DRGs, and its suppression lessened actin and microtubule defects, improved axonal transport, and prevented neurodegeneration. These findings suggest that Rac1 overactivation plays a central role in initiating axonal damage in hATTR-PN.
To assess whether this mechanism is also relevant in people, the team analyzed genetic data from 175 hATTR-PN patients. They identified a genetic variant in the RACGAP1 gene that was significantly associated with a late disease onset, specifically “a mean increase of 20 years for [people carrying the variant in one copy of the gene] and 34 years for [those carrying the variant in both gene copies],” the team wrote.
The variant was found to increase the production of RacGAP1, a protein that suppresses Rac1 activity, supporting the idea that lower Rac1 activity may protect axons in hATTR-PN.
“Although we cannot disclose the primary defect induced by [transthyretin clumps], our data suggest that a common pathway mediates the damage to actin and microtubules in [hATTR-PN], driven by Rac1,” the researchers wrote. Targeting Rac1-mediated pathways may therefore be a potential treatment strategy for the rare condition, with “Rac1 inactivation leading to a lower rate of neurodegeneration.”
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