New Model for Studying Parkinson's: Swiss Researchers Develop New, Working Mammalian Model to Combat Genetic Causes of the Disease

ScienceDaily (Mar. 22, 2011) — Evidence is steadily mounting that genetic factors play an important role in many cases of Parkinson's disease (PD). In a study published February 2, 2011, online in the Journal of Neuroscience, researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland report a new mammalian model for studying a specific gene mutation commonly found in PD sufferers, opening the door to new drugs to fight the malady.

This is a cervical slice showing the healthy left-hand side of the brain and the damaged, Parkinson's disease side with lesions provoked by the LKKR2 gene mutation. 

"This is a great step forward toward a more comprehensive understanding of how the disease works, and how it can be diagnosed and treated," explains neuroscientist and EPFL President Patrick Aebischer, lead author of the study.

PD is a common neurodegenerative disease that greatly reduces quality of life and costs the United States around 23 billion dollars a year. Until now, researchers have encountered difficulty in reproducing PD pathology in animals because of an incomplete understanding of the disease.

Recently, a mutation of the gene coding for LRRK2, a large enzyme in the brain, has emerged as the most prevalent genetic cause of PD (genetics are implicated in about 10 percent of all PD cases). When the enzyme is mutated, it becomes hyperactive, causing the death of vulnerable neurons and leading to a reduction in levels of the brain neurotransmistter dopamine. This decrease in dopamine eventually triggers the symptoms characteristic of Parkinson's, such as tremors, instability, impaired movement, and later stage dementia.

Now, with funding from the Michael J. Fox Foundation for Parkinson's Research, Aebischer and his team in the Neurodegenerative Studies Laboratory at EPFL, have successfully introduced mutant LRRK2 enzyme into one hemisphere of a rat brain, resulting in the same PD manifestations that occur in humans in one side of the rodent's body. To do this, the researchers spent two years producing and optimizing a viral vector to deliver mutated, LRRK2 coding DNA into the rat brain. LRRK2 is a large and complicated enzyme and designing a vector capable of transporting its extremely long genetic code was no small feat.

The new animal model developed by EPFL is sure to benefit future Parkinson's research. The fact that LRRK2 is an enzyme -- a catalyzing protein involved in chemical reactions -- makes it drug accessible and therefore of specific interest to researchers looking for neuroprotective strategies, or pharmaceutical treatments that halt or slow disease progression by protecting vulnerable neurons. Armed with the LRRK2 model, new pharmaceuticals that inhibit the hyper-activity of the enzyme could one day prevent the destructive chain of events that leads to neurodegeneration and devastation in many with PD.

Potential Way to Protect Neurons in Parkinson's, Alzheimer's, ALS

ScienceDaily (Mar. 14, 2011) — Cell biologists pondering the death of neurons -- brain cells -- have now shown that by eliminating one ingredient from the cellular machinery, they prolonged the life of neurons stressed by a pesticide chemical. The finding identifies a potential therapeutic target to slow changes that lead to neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

This is an illustration of a healthy neuron. A UT Health Science Center San Antonio study found a protective mechanism for neurons placed under mitochondrial stress.

The researchers, from The University of Texas Health Science Center San Antonio, found that neurons lacking a substance called caspase-2 were better able to withstand pesticide-induced damage to energy centers known as mitochondria.

Master switch

Caspase-2 appears to be a master switch that can trigger either cell death or survival depending on the amount of cellular damage, the team found. Neurons that lacked caspase-2 showed an increase in protective activities, including the efficient breakdown of obsolete or used proteins. This process, called autophagy, delays cell death.

"This research shows, for the first time, that in the absence of caspase-2 neurons increase autophagy to survive," said study co-author Marisa Lopez-Cruzan, Ph.D., investigator in the cellular and structural biology department at the Health Science Center.

Role of energy centers

Evidence suggests that mitochondrial dysfunction plays an important role in neuronal death in conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Huntington's disease.

"Identifying initiators in the cell death process is important for determining therapeutic approaches to provide the maximum protection of neurons during neurodegenerative conditions," said senior author Brian Herman, Ph.D., vice president for research and professor of cellular and structural biology at the Health Science Center.

Young adult mice

The team studied neurons from young adult mice. This was intended to model the early changes that take place in neurodegenerative diseases.

The research is in the March 11 issue of the Journal of Biological Chemistry.

Dr. Lopez-Cruzan, director of Dr. Herman's laboratory, came up with the idea that caspase-2 protects cells from mitochondrial stress. Meenakshi Tiwari, Ph.D., postdoctoral fellow, expanded upon the initial work and is first author of the paper.

The work was supported by the National Institute on Aging and is part of a second National Institutes of Health MERIT award to Dr. Herman.