Writing in the Journal of Clinical Investigation, the team noted that the flavonoid compound which is found in certain fruit and vegetables could help to prevent damage to the nerves associated with spinal muscular atrophy (SMA) – which is the childhood form of motor neurone disease (ALS) by preventing nerve damage.
Led by Professor Tom Gillingwater from the University of Edinburgh UK, the team explained that a gene mutation associated with SMA affects vital cellular processes that help to remove unwanted molecules from cells in the body. When this process doesn't work properly, certain molecules can build-up and cause problems inside the cells, said the researchers.
The build-up of a specific molecule called beta-catenin inside cells is responsible for some of the symptoms associated with the condition, they explained – noting that animal studies have shown that the use of purified quercetin – which targets beta-catenin – led to a significant improvement in the health of nerve and muscle cells.
"By working to understand how SMA operates at a molecular level we have been able to apply a naturally occurring compound which targets the one of the key culprits,” said study co-author Dr Iain Robinson from the University of Plymouth and the Peninsula Schools of Medicine and Dentistry, UK.
"This is an important step that could one day improve quality of life for the babies affected by this condition and their families,” added Gillingwater, who added that although quercetin did not prevent all of the symptoms associated with SMA, the team hopes that it could offer a useful option in the early stages of disease.
Study details
The team used a mouse models of SMA, to identify the key molecular pathways that are responsible for regulating neuromuscular and systemic pathology in SMA.
“We observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1),” explained the team – adding that survival motor neuron (SMN) protein physically interacted with UBA1 in neurons.
Indeed, suppression of UBA1 was sufficient to produce an SMA-like neuromuscular condition in zebrafish, the team noted – adding that this suggests that UBA1 directly contributes to disease pathogenesis.
“Dysregulation of UBA1 and subsequent ubiquitination pathways led to beta-catenin accumulation,” wrote Gillingwater.
Reversal of this process, leading to the removal of beta-catenin from cells ‘robustly ameliorated’ the SMA-like neuromuscular conditions in zebrafish, Drosophila, and mouse models, they said.
“Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent beta-catenin signalling, highlighting ubiquitin homeostasis and beta-catenin as potential therapeutic targets for SMA,” they said.
Source: Journal of Clinical Investigation
Published online ahead of print, doi: 10.1172/JCI71318
“Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy”
Authors: Thomas M. Wishart, Chantal A. Mutsaers, et al