Posts tagged LRRK2

Mutations in a gene called LRRK2 carry a well-established risk for Parkinson’s disease, however the basis for this link is unclear.

(Image caption: A microscope image of a cultured cell)

The team, led by Parkinson’s UK funded researchers Dr Kurt De Vos from the Department of Neuroscience and Dr Alex Whitworth from the Department of Biomedical Sciences, found that certain drugs could fully restore movement problems observed in fruit flies carrying the LRRK2 Roc-COR Parkinson’s mutation.

These drugs, deacetylase inhibitors, target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study is published in Nature Communications.

Dr De Vos, a Lecturer in Translational Neuroscience at the world-leading Sheffield Institute for Translational Neuroscience (SITraN), said: “Our study provides compelling evidence that there is a direct link between defective transport within nerve cells and movement problems caused by the LRRK2 Parkinson’s mutation in flies.”

Co-investigator Dr Alex Whitworth explained: “We could also show that these neuronal transport defects caused by the LRRK2 mutation are reversible.

“By targeting the transport system with drugs, we could not only prevent movement problems, but also fully restore movement abilities in fruit flies who already showed impaired movement marked by a significant decrease in both climbing and flight ability.”

The LRRK2 gene produces a protein that affects many processes in the cell. It is known to bind to the microtubules, the cells’ transport tracks. A defect in this transport system has been suggested to contribute to Parkinson’s disease. The researchers have investigated this link and have now found the evidence that certain LRRK2 mutations affect transport in nerve cells which leads to movement problems observed in the fruit fly (Drosophila).

The team then used several approaches to show that preventing the association of the mutant LRRK2 protein with the microtubule transport system rescues the transport defects in nerve cells, as well as the movement deficits in fruit flies.

Dr De Vos added: “We successfully used drugs called deacetylase inhibitors to increase the acetylated form of α-tubulin within microtubules which does not associate with the mutant LRRK2 protein. We found that increasing microtubule acetylation had a direct impact on cellular axonal transport.
“These are very promising results which point to a potential Parkinson’s therapy. However, further studies are needed to confirm that this rescue effect also applies in humans.“

Dr Beckie Port, Research Communications Officer at Parkinson’s UK, which helped to fund the study, said: “This research gives hope that, for people with a particular mutation in their genes, it may one day be possible to intervene and stop the progression of Parkinson’s.

“The study has only been carried out in fruit flies, so much more research is needed before we know if these findings could lead to new treatment approaches for people with Parkinson’s.”

(Source: sheffield.ac.uk)

Working with human neurons and fruit flies, researchers at Johns Hopkins have identified and then shut down a biological process that appears to trigger a particular form of Parkinson’s disease present in a large number of patients. A report on the study, in the April 10 issue of the journal Cell, could lead to new treatments for this disorder.

“Drugs such as L-dopa can, for a time, manage symptoms of Parkinson’s disease, but as the disease worsens, tremors give way to immobility and, in some cases, to dementia. Even with good treatment, the disease marches on,” says Ted Dawson, M.D., Ph.D., professor of neurology and director of the Johns Hopkins Institute for Cell Engineering, Dawson says the new research builds on a growing body of knowledge about the origins of Parkinson’s disease, whose symptoms appear when dopamine-producing nerve cells in the brain degenerate. Further evidence for a role of genetics in Parkinson’s disease appeared a decade ago when researchers identified key mutations in an enzyme known as leucine-rich repeat kinase 2, or LRRK2 — pronounced “lark2.” When that enzyme was cloned, Dawson, together with his wife and longtime collaborator Valina Dawson, Ph.D., professor of neurology and member of the Institute for Cell Engineering, discovered that LRRK2 was a kinase, a type of enzyme that transfers phosphate groups to proteins and turns proteins on or off to change their activity.

Over the years, it was found that blocking kinase activity in mutated LRRK2 halted degeneration, while enhancing it made things worse. But nobody knew what proteins LRRK2 was acting on.

"For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson’s disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke. "This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson’s disease."

Dawson went fishing for the right proteins using LRRK2 as bait. When his team began to identify those proteins, Dawson says they were surprised to discover that many were linked to the cellular machinery, like ribosomes, that make proteins. Nobody, says Dawson, suspected that LRRK2 might be involved at such a basic level as protein manufacture.

Unsure if they were right, the team then tested the proteins they identified to see which of them, if any, LRRK2 could add phosphate groups to. They came up with three ribosomal protein candidates — s11, s15 and s27. They then altered each ribosomal protein to see what would happen. It turned out that mutating s15 in a manner that blocked LRRK2 phosphorylation protected nerve cells taken from rats, humans and fruit flies from death. In other words, s15 appeared to be the much sought-after target of LRRK2, Dawson says.

"When you go fishing, you want to catch fish. We just happened to catch a big one,” Dawson says.

With the protein now identified, Dawson’s team is tackling further experiments to find out how excess protein production causes dopamine neurons to degenerate. And they want to see what happens when they block LRRK2 from phosphorylating the s15 protein in mice, to build on their findings from fruit flies and nerve cells grown in a dish.

“There’s a big chasm between animal disease models and human treatments,” says Ian Martin, Ph.D., a neuroscientist in Dawson’s lab and the lead author on the paper. “But it’s exciting. I think it definitely could turn into something real, hopefully in my lifetime.”

(Source: hopkinsmedicine.org)