The study, “Protein synthesis is suppressed in sporadic and familial Parkinson’s disease by LRRK2,” was published in The FASEB Journal.
The LRRK2 protein (leucine-rich repeat kinase 2), also known as dardarin, plays an important role in cellular metabolism, such as autophagy (the cell’s recycling and waste-disposal system) and mitochondrial activity that provides energy to cells.
Mutations in the LRRK2 gene, which provides instructions for the LRRK2 enzyme, are one of the most common genetic causes of Parkinson’s disease. The LRRK2 protein also is overly active in many Parkinson’s cases with no known genetic link (sporadic disease).
Recent evidence has suggested that LRRK2 can regulate protein synthesis, or the production of new proteins. Additionally, Parkinson’s-associated mutations in this enzyme are thought to be implied in the dysregulation of this process by directly interfering with ribosomes, the cells’ protein-building machinery.
To understand the role of LRRK2 in the development of familial (genetic) and sporadic Parkinson’s, researchers at University of Turku and Åbo Akademi University, in Finland, recently monitored protein synthesis in animal and cellular models of the disease.
Researchers used rotenone, a pesticide known to inhibit the function of mitochondria and to induce oxidative stress (the imbalance between the production and clearance of toxic reactive species that are harmful to cells) to induce Parkinson’s-like symptoms in rodent neurons.
Rotenone increased LRRK2 activity, repressing protein synthesis and causing nerve cells to atrophy. However, when adding LRRK2 inhibitors, this effect was reversed. Furthermore, in mice lacking the LRRK2 gene, protein synthesis increased.
The team then examined two brain areas involved in motor control that are severely affected in Parkinson’s disease — the striatum and the substantia nigra — to better understand LRRK2 activity.
LRRK2 works as an enzyme with kinase activity. These type of proteins (kinases) assist in the transfer of a phosphate group — a molecule made of oxygen and phosphorus — to certain proteins. Such modification is called phosphorylation and is an essential step in turning on and off many proteins inside the cell.
In rotenone-treated mice, researchers found phosphate marks in key checkpoint sites within these brain regions that signaled the cell to stop producing proteins.
Next, researchers analyzed skin cells obtained from the forearms of Parkinson’s patients, both with sporadic and familial disease. They observed that protein synthesis was reduced (by 40% or more) in cells from patients with both sporadic and familial forms of the disease, when compared to cells from healthy donors of a similar age.
However, when adding LRRK2 inhibitors protein synthesis returned to control levels, indicating that “LRRK2 activity was responsible for reduced protein synthesis not only in [familial] cases, but also in sporadic subjects,” the researchers wrote.
Importantly, when researchers analyzed skin samples from individuals who were not fully diagnosed at the time of sampling, but who progressed to have a clinical diagnosis of Parkinson’s within two years, they observed the same trend of reduced protein synthesis.
“These data indicate that repressed protein synthesis provides a specific biomarker readout of Parkinson’s disease from patient cells even at an early stage,” the researchers wrote.
Importantly, in cells from multiple system atrophy patients, a condition distinct from Parkinson’s but with overlapping symptoms, researchers found no evidence of decreased protein synthesis. This indicates that protein synthesis reduction may be specific to Parkinson’s disease.
“These results are interesting because LRRK2 is thought to contribute to Parkinson’s disease, but precisely how, it is not yet known” Eleanor Coffey, PhD, lead study author, said in a press release.
The team also found that the decline in protein production was linked to aging, becoming progressively more inhibited in Parkinson’s patients 60 and older. This was not observed in healthy, aging individuals.
“This fits with the theory that Parkinson’s disease is an accelerated form of aging, and suggests that reduced translation in Parkinson’s disease may represent accelerated aging,” the researchers wrote.
The team now is analyzing patient samples to understand which specific protein groups are present at lower levels so they can identify which can become biomarkers to monitor disease progression, allowing early detection of Parkinson’s.
“If such a signature can be found, it could help improve clinical trial outcome by providing a tool for patient stratification. If successful, this would help accelerate the development of better treatments for Parkinson’s disease patients,” the researchers concluded.
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