PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Unique protein interaction may drive most common genetic cause of Parkinson's disease

Gladstone findings challenge conventional wisdom; point to new therapeutic strategies

2014-01-08
(Press-News.org) Contact information: Anne Holden
anne.holden@gladstone.ucsf.edu
415-734-2534
Gladstone Institutes
Unique protein interaction may drive most common genetic cause of Parkinson's disease Gladstone findings challenge conventional wisdom; point to new therapeutic strategies

San Francisco, CA—January 7, 2013—The most devastating aspect of Parkinson's disease may not be its debilitating symptoms, which rob its victims of their ability to control their own movement. It may not be the millions around the world and their families who suffer each day from the disease's harmful effects. Instead, it may in fact be that its root causes remain largely a mystery. But now, scientists at the Gladstone Institutes have discovered how the interplay between two proteins in the brain fuels the degradation and death of the class of brain cells, or neurons, that leads to Parkinson's. These findings, which stand in stark contrast to conventional wisdom, lay much-needed groundwork for developing treatments that target the disease's elusive underlying mechanisms.

In the latest issue of the Journal of Neuroscience, now available online, scientists in the laboratory of Gladstone Investigator Steve Finkbeiner, MD, PhD, harnessed the power of their one-of-a-kind robotic microscope to track the lifespan of individual neurons over time. The microscope has been used to study a variety of neurodegenerative diseases, and in this study, they focus their attention on LRRK2—the most common genetic cause of Parkinson's.

Scientists have long known that mutations in LRRK2 cause misfolded versions of the LRRK2 protein to accumulate in neurons. The prevailing hypothesis has been that misfolded LRRK2 boosts the activity of a type of enzyme called kinase, and that this heightened kinase activity is what drives cell death. Scientists have also looked to the fact that mutant LRRK2 tends to clump together into so-called inclusion bodies (IB's) as another contributor to the disease's progression.

"As a result, researchers have used the presence of IB's and heightened kinase activity as a proxy for measuring LRRK2's harmful effects, rather than measuring LRRK2 levels directly," explained Dr. Finkbeiner, who is the associate director of neurological research at Gladstone as well as a professor at the University of California, San Francisco, with which Gladstone is affiliated. "But we were unconvinced that these were the main drivers of cell death—so we decided to take a closer look at what was happening inside the cell."

When studying neurodegenerative diseases such as Parkinson's, which are defined by the degradation and death of neurons, traditional tools usually only allow researchers to track neuronal death at the population level. But Dr. Finkbeiner's revolutionary microscope enables researchers to follow the lives of thousands of individual neurons—offering the clearest view into which events during the lifetime of the cell play a role in its death.

The researchers generated neurons from two sources: from rats genetically modified to have mutant LRRK2, and human neurons derived from the skin cells of LRRK2-related Parkinson's patients. They then tracked these cells over time, monitoring the buildup of mutant LRRK2 and how that buildup led to cell death.

"Interestingly, we found that neither IB's nor kinase activity were the direct cause of cellular toxicity leading to neuronal death,," said Gladstone Staff Research Scientist Gaia Skibinski, PhD, the paper's lead author. "Instead, the underlying cause of cell death appeared to be tied directly to the accumulation of diffuse mutant LRRK2."

But as the research team peered even closer into the lives of these neurons, they found something intriguing: a unique interplay between mutant LRRK2 and alpha-synuclein, another protein that has long been associated with Parkinson's. Research has shown that Parkinson's patients with LRRK2 mutations often show an abnormal accumulation of alpha-synuclein. But until now, the exact nature of the relationship between these two proteins remained unclear.

"Importantly, we found that in both the rat and human cellular models, removing alpha-synuclein reduced cell death caused by mutant LRRK2," continued Dr. Skibinski. "When we looked closer, we found that loss of alpha-synuclein led to an immediate drop in LRRK2."

The team hypothesizes that, in patients with mutant LRRK2, the build-up of alpha-synuclein hinders the cell's ability to clear away LRRK2, leading to its accumulation. Over time, the buildup of LRRK2 becomes toxic to the cell, and the cell dies.

"The discovery of a synergistic relationship between two proteins long known to play a role in Parkinson's is a huge step towards developing drugs that attack the disease's underlying mechanisms," said Dr. Finkbeiner. "As we continue to unravel the precise functional relationship between alpha-synuclein and LRRK2, we are well on our way to halting the onslaught of Parkinson's on the brain."



INFORMATION:

Gladstone Investigator Ken Nakamura, MD, PhD, and the National Institutes of Health Investigator Mark Cookson, PhD, also participated in this research, which was supported by the following: the DeClerg Family, the National Center for Research Resources (#RR189288), the Burroughs-Wellcome Medical Scientist Fund, the National Institute of Neurological Disorders and Stroke (#P30NS069496), the National Institute on Aging, the Koret/Taube Center, the Hellmen Family Foundation, the California Institute for Regenerative Medicine (#RB4-06079) and the National Institutes of Health (#U24 NS078370, #3R01 NS039074, #2R01 NS04549).

About the Gladstone Institutes

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of California, San Francisco.



ELSE PRESS RELEASES FROM THIS DATE:

Survival protein a potential new target for many cancers

2014-01-08
Survival protein a potential new target for many cancers Walter and Eliza Hall Institute researchers have discovered a promising strategy for treating cancers that are caused by one of the most common cancer-causing changes in cells. The discovery offers ...

Fit teenagers are less likely to have heart attacks in later life

2014-01-08
Fit teenagers are less likely to have heart attacks in later life Researchers in Sweden have found an association between a person's fitness as a teenager and their risk of heart attack in later life. In a study of nearly 750,000 men, they found that the more aerobically ...

Fight or flight and the evolution of pain

2014-01-08
Fight or flight and the evolution of pain Recent highlights in Molecular Biology and Evolution Hard wired into the survival mechanisms of all animals is the perception of pain. Different stimuli, such as heat or cold, foul odors, ...

Mega-landslide in giant Utah copper mine may have triggered earthquakes

2014-01-08
Mega-landslide in giant Utah copper mine may have triggered earthquakes January 2014 GSA Today science article Boulder, Colorado, USA – Landslides are one of the most hazardous aspects of our planet, causing billions of dollars in damage and thousands of deaths each year. ...

Of lice and men (and chimps): Study tracks pace of molecular evolution

2014-01-08
Of lice and men (and chimps): Study tracks pace of molecular evolution CHAMPAIGN, Ill. — A new study compares the relative rate of molecular evolution between humans and chimps with that of their lice. The researchers wanted to know whether evolution ...

Is multitasking mastery in the genes?

2014-01-08
Is multitasking mastery in the genes? Human factors/ergonomics researchers have long studied the connection between cognitive function and the ability to perform well on multiple simultaneous tasks, and recently a group of neuroergonomics researchers went a ...

Childhood fractures may indicate bone-density problems

2014-01-08
Childhood fractures may indicate bone-density problems ROCHESTER, Minn. — Broken bones may seem like a normal part of an active childhood. About 1 in 3 otherwise healthy children suffers a bone fracture. Breakage of the bone running from the elbow to the thumb side of the ...

Combined therapy benefits cigarette smokers trying to quit compared to monotherapy

2014-01-08
Combined therapy benefits cigarette smokers trying to quit compared to monotherapy ROCHESTER, Minn. — Jan. 7, 2014 — Among cigarette smokers, combining the smoking cessation medications varenicline and bupropion, compared with varenicline alone, resulted in higher smoking ...

New diagnostic and therapeutic techniques show potential for patients with metastasized melanoma

2014-01-08
New diagnostic and therapeutic techniques show potential for patients with metastasized melanoma Reston, Va. (January 7, 2014) – With low survival rates for patients with metastasized melanoma, accurate staging and effective treatments are critical to extending ...

Pandora's magnifying glass

2014-01-08
Pandora's magnifying glass First image from Hubble's Frontier Fields This image of Abell 2744 is the first to come from Hubble's Frontier Fields observing programme, which is using the magnifying power of enormous galaxy clusters to peer deep ...

LAST 30 PRESS RELEASES:

Scientists track evolution of pumice rafts after 2021 underwater eruption in Japan

The future of geothermal for reliable clean energy

Study shows end-of-life cancer care lacking for Medicare patients

Scented wax melts may not be as safe for indoor air as initially thought, study finds

Underwater mics and machine learning aid right whale conservation

Solving the case of the missing platinum

Glass fertilizer beads could be a sustained nutrient delivery system

Biobased lignin gels offer sustainable alternative for hair conditioning

Perovskite solar cells: Thermal stresses are the key to long-term stability

University of Houston professors named senior members of the National Academy of Inventors

Unraveling the mystery of the missing blue whale calves

UTA partnership boosts biomanufacturing in North Texas

Kennesaw State researcher earns American Heart Association award for innovative study on heart disease diagnostics

Self-imaging of structured light in new dimensions

Study highlights successes of Virginia’s oyster restoration efforts

Optimism can encourage healthy habits

Precision therapy with microbubbles

LLM-based web application scanner recognizes tasks and workflows

Pattern of compounds in blood may indicate severity of gestational hypertension and preeclampsia

How does innovation policy respond to the challenges of a changing world?

What happens when a diet targets ultra-processed foods?

University of Vaasa, Finland, conducts research on utilizing buildings as energy sources

Stealth virus: Zika virus builds tunnels to covertly infect cells of the placenta

The rising tide of sand mining: a growing threat to marine life

Contemporary patterns of end-of-life care among Medicare beneficiaries with advanced cancer

Digital screen time and nearsightedness

Postoperative weight loss after anti-obesity medications and revision risk after joint replacement

New ACS research finds low uptake of supportive care at the end-of-life for patients with advanced cancer

New frailty measurement tool could help identify vulnerable older adults in epic

Co-prescribed stimulants, opioids linked to higher opioid doses

[Press-News.org] Unique protein interaction may drive most common genetic cause of Parkinson's disease
Gladstone findings challenge conventional wisdom; point to new therapeutic strategies