(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.
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
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:
Fat may play an important role in brain metabolism
New study finds no lasting impact of pandemic pet ownership on human well-being
New insights on genetic damage of some chemotherapies could guide future treatments with less harmful side effects
Gut microbes could protect us from toxic ‘forever chemicals’
Novel modelling links sea ice loss to Antarctic ice shelf calving events
Scientists can tell how fast you're aging from a single brain scan
U.S. uterine cancer incidence and mortality rates expected to significantly increase by 2050
Public take the lead in discovery of new exploding star
What are they vaping? Study reveals alarming surge in adolescent vaping of THC, CBD, and synthetic cannabinoids
ECMWF - delivering forecasts over 10 times faster and cutting energy usage by 1000
Brazilian neuroscientist reveals how viral infections transform the brain through microscopic detective work
Turning social fragmentation into action through discovering relatedness
Cheese may really be giving you nightmares, scientists find
Study reveals most common medical emergencies in schools
Breathable yet protective: Next-gen medical textiles with micro/nano networks
Frequency-engineered MXene supercapacitors enable efficient pulse charging in TENG–SC hybrid systems
Developed an AI-based classification system for facial pigmented lesions
Achieving 20% efficiency in halogen-free organic solar cells via isomeric additive-mediated sequential processing
New book Terraglossia reclaims language, Country and culture
The most effective diabetes drugs don't reach enough patients yet
Breast cancer risk in younger women may be influenced by hormone therapy
Strategies for staying smoke-free after rehab
Commentary questions the potential benefit of levothyroxine treatment of mild hypothyroidism during pregnancy
Study projects over 14 million preventable deaths by 2030 if USAID defunding continues
New study reveals 33% gap in transplant access for UK’s poorest children
Dysregulated epigenetic memory in early embryos offers new clues to the inheritance of polycystic ovary syndrome (PCOS)
IVF and IUI pregnancy rates remain stable across Europe, despite an increasing uptake of single embryo transfer
It takes a village: Chimpanzee babies do better when their moms have social connections
From lab to market: how renewable polymers could transform medicine
Striking increase in obesity observed among youth between 2011 and 2023
[Press-News.org] Unique protein interaction may drive most common genetic cause of Parkinson's diseaseGladstone findings challenge conventional wisdom; point to new therapeutic strategies