Researcher: Cause and Treatment for Parkinson's "In Our Sights"

Scientists optimistic after discovering genetic link to loss of dopamine-producing neurons

By Nikhil Swaminathan

News - December 13, 2007

http://www.sciam.com/article.cfm?id=...nsons-in-sight

A successful treatment for Parkinson's disease, a neurodegenerative disorder that affects 1 percent of the world's population and (an estimated 500,000 people in the U.S.) aged 60 years and over, may be "in our sights now," says Ronald McKay, a researcher at the National Institutes of Health (NIH).

McKay's optimism stems from new research that shows that a gene, known as forkhead box A2 (FOXA2), is responsible for the differentiation and spontaneous destruction of neurons that secrete the neurotransmitter dopamine, a cell population that is progressively lost in Parkinson's disease, which is characterized by tremors, loss of muscle control and speech difficulties.

"We have the cells; we know what controls their birth and death—we're on our way," says McKay, a senior molecular biology investigator. "It looks like we've got this disease in our sights now. We will understand Parkinson's disease relatively soon."

McKay and colleagues (at the NIH's National Institute of Neurological Disorders and Stroke in Bethesda, Md., and at Northwestern University's Feinberg School of Medicine in Chicago) report in the journal PLoS Biology that they tested candidate cells in the brain of embryonic mice to determine which ones produce the enzyme tyrosine hydroxylase, a compound manufactured by dopamine neurons to help convert amino acids into precursors of the neurotransmitter.

The team found that such cells are created at the floor plate, a tubular cluster of cells located near the spinal cord, which organizes the developing brain by signaling immature, precursor cells to differentiate into neurons that play a particular role.

"The floor plate gives rise directly to dopamine neurons; it isn't just an organizer, but it's also itself a precursor cell," McKay says.

While examining the floor plate to determine when new dopamine neurons are created (and thereby when tyrosine hydroxylase signals can be detected), researchers also discovered high levels of FOXA2, the transcription factor coded by the FOXA2 gene.

"If you increase the expression [effect] of FOXA2, you get more dopamine neurons in the lab," McKay says, noting that when they upped the amount of FOXA2 in a tissue culture it triggered the creation of six times as many dopamine-producing nerve cells as normally present.

In addition, researchers observed spontaneous degeneration of dopaminergic neurons in the substantia nigra (a midbrain region associated with both pleasure and movement) in transgenic mice created without the usual two copies of the FOXA2 gene. (Animals normally receive a copy of the gene from each parent.) Substantia nigra nerve cells send dopamine to the striatum, another midbrain structure, which regulates the planning of movement. The erosion of these cells began after the mice turned 18 months old, which is akin to the age at which Parkinson's most often strikes humans.

Just as in humans, the loss of cells was unequal in the two brain spheres, resulting in asymmetric motor difficulties, such as stiffness on the right side but not the left.

"In the case of Parkinson's, although we know 10 genes involved in the disease, we don't have a good experimental model that is like the cell loss that you see in Parkinson patients," McKay says. "In these animals we do see this, we see a spontaneous loss of the same dopaminergic neurons that are seen in Parkinson's disease."

Serge Przedborski, co-director of Columbia University's Center for Motor Neuron Biology and Disease, praised the findings but noted that the new model was more useful in some circumstances than in others, An expert in Parkinson's mouse models induced by a toxin known as MPTP—which causes Parkinsonian symptoms when injected into animals—he believes the new model will be more useful in studying plasticity (the strengthening and weakening of neuronal connections) in a neurodegenerative brain. If a researcher wants to study the mechanism of cell death, he adds, an MPTP model should suffice.
McKay says that combining the toxin and genetic models may be the best way to "generate a comprehensive understanding of the disease" The bottom line, he says: "I think there's reason to be optimistic here."

Gene research is promising ..
Trying to see a fuller picture ! I have gone back to a past thread by Carolyn where by gene research is used to get rid of "poisons" from brain cells :

http://neurotalk.psychcentral.com/thread35322.html

" NEW YORK, Jan. 4 — The Michael J. Fox Foundation has committed up to $3.8 million for the development of a gene silencing therapeutic to treat Parkinson's disease by reducing expression of the protein alpha-synuclein. A team of researchers led by Matt Farrer, PhD, of Mayo Clinic Jacksonville (Florida) with collaborators at Alnylam Pharmaceuticals and The Parkinson's Institute and Clinical Center will work to optimize a small interfering RNA (siRNA)-based therapeutic that could slow or stop the progression of Parkinson's disease. If successful, the project could result in an entirely new class of drug targeting the alpha-synuclein gene, which has proved difficult to modulate using traditional small-molecule therapeutics."

The siRNA approach to studying the function of different proteins has been revolutionary. It is based on the discovery of the existence of naturally occuring small RNA (ribonucleic acid) molecules which appear to function as normal physiological regulators of the production of many key enzymes and other proteins. The neat thing about this concept as a laboratory tool is that one can order from suppliers synthetic siRNAs made to order to inhibit the production in living cells of just about any protein one chooses.

The last series of experiments I am involved in for my research career utilizes this technology in order to study the relationship between two important proteins in the extracellular matrix, fibronectin and collagen, while they are still inside the cells that produce them. We are using human lung fibroblasts.

I met Matt Farrer when he visited our medical center four years ago. At that time his group at the Mayo in Florida was involved in discovering the LRRK protein mutations which are one of the causes of genetically transmitted Parkinson's. He is an impressive young scientist who could just nail the best PD treatment with this siRNA approach.