The characteristic toxic buildup of mutant transthyretin (TTR) protein clumps in familial amyloid polyneuropathy (FAP) affects the development of nerve cell fibers by interacting with regulators of a protein called actin, according to a study in a fruit fly model of the disease.
The data suggested that actin alterations may underlie TTR-induced neurodegeneration and highlighted actin regulators called Rho GTPases as potential therapeutic targets in FAP.
Still, further studies in FAP mouse models are needed to confirm these findings and Rho GTPases’ potential, the researchers noted.
The study, “Transthyretin interacts with actin regulators in a Drosophila model of familial amyloid polyneuropathy,” was published in the journal Scientific Reports.
FAP, also known as hereditary ATTR amyloidosis, is caused by mutations in the TTR gene that result in the production of a faulty TTR protein. This leads to the formation and buildup of damaging TTR clumps in tissues, mainly the nerves, heart, kidneys, and eyes.
Increasing evidence suggests that an abnormal regulation of cytoskeletal proteins contribute to nerve cell, or neuron loss in neurodegenerative diseases. The cytoskeleton is a network of filaments or fibers, including actin, that regulates the cell’s shape and movement, as well as the transport of molecules within the cell. Of note, actin is a protein that joins together many small molecules to form long filaments.
The growth of both longer (axons) and shorter (dendrites) neuron fibers — essential for nerve cell development and function — is regulated by the growth cone, a cellular structure composed of cytoskeletal proteins, including actin.
“However, the molecular mechanisms underlying TTR-induced neurodegeneration are still unclear, despite the extensive studies in vertebrate models,” the researchers wrote.
Now, researchers at the Institute for Molecular and Cell Biology and the Institute for Research and Innovation in Health, both in Portugal, discovered that clumps of mutant TTR interact with regulators of actin dynamics, affecting nerve fiber growth, and likely contributing to neuronal death.
A fruit fly (Drosophila melanogaster) model of FAP was used to produce the resulting TTR protein of the TTR Val30Met mutation — the most common variant associated with FAP — specifically in the eye’s retina.
This model recapitulated several FAP features, such as gradual accumulation of TTR clumps, progressive loss of motor skills, and reduced lifespan.
The team hypothesized that soluble TTR produced in the flies’ retina enters circulation, “where it forms soluble aggregates [clumps] inducing neurotoxicity in adjacent tissues like the brain, leading to impaired neuronal function.”
This is in line with what happens in vertebrates, in which TTR produced in the liver and brain can reach other tissues through the blood and cerebrospinal fluid, which is the liquid that surrounds the brain and spinal cord.
The researchers also found that these flies showed progressive eye defects and axon abnormalities, as well as problems in the actin structure within growth cones, suggesting altered actin organization.
A genetic screen focused on members of the Rho GTPase signaling pathways — major players in actin dynamics and implicated in several neurodegenerative disorders — was then conducted. The aim was to assess whether they acted as modifiers of TTR-induced neurodegeneration.
The results showed that blocking two Rho GTPases, specifically Rho1 and Rok, increased eye and axon defects in these flies. Meanwhile, suppressing the Rac/Cdc42/Pak/LIMK pathway had the opposite effect, lessening neurodegeneration.
“Our data uncovered Rho GTPase signaling pathways as novel players in the molecular mechanisms through which [mutated TTR] potentially induces neurotoxicity,” the researchers wrote.
Mutated TTR likely interacts with Rho pathway members through signaling, as the team failed to detect a direct interaction between them.
“Based on these findings we propose that actin cytoskeleton alterations may mediate the [axon defects] observed in FAP patients, and highlight a molecular pathway, mediated by Rho GTPases, underlying TTR-induced neurodegeneration,” the team wrote.
They added that modulators of Rho GTPase pathways may have a beneficial impact on FAP, namely previously identified Rac1 and Cdc42 suppressors.
“Nevertheless, future research will address the significance of Rho GTPase signaling pathways in FAP mouse models, that will contribute to increase the knowledge on the [development] of the disease,” the team concluded.
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