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

NEED FOXA2 TO LIVE: Scientists find that insufficient copies of the gene FOXA2 cause dopamine neurons, which die off during Parkinson's disease, to spontaneously degenerate.


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.

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Anybody else notice the perfect irony of this gene being designated the FOXA2 gene??!!

The Ubiquitin Proteasome Pathway (UPP) is the principal mechanism for protein catabolism in the mammalian cytosol and nucleus. The highly regulated UPP affects a wide variety of cellular processes and substrates and defects in the system can result in the pathogenesis of several important human diseases. The central role of the UPP in biology has been recognized with the Nobel Prize for Chemistry which was awarded to Avram Hershko, Aaron Ciechanover and Irwin Rose in 2004.


The UPP is central to the regulation of almost all cellular processes including:

Antigen processing
Apoptosis
Biogenesis of organelles
Cell cycle and division
DNA transcription and repair
Differentiation and development
Immune response and inflammation
Neural and muscular degeneration
Morphogenesis of neural networks
Modulation of cell surface receptors, ion channels and the secretory pathway
Response to stress and extracellular modulators
Ribosome biogenesis
Viral infection

when you steal info from one individuals work they call it "Plagiarism"
-
when you steal from many -it's called research!
_________
peace,
tena


Oct. 6 2004 Press Contact: John Easton



Alumnus Irwin Rose receives 2004 Nobel Prize in chemistry
Photo:
Irwin Rose, 1995


--------------------------------------------------------------------------------

University of Chicago
Nobel Laureates

In the News:
“Californian, 2 Israelis share Nobel / Prize in chemistry for uncovering how cells shed unwanted proteins”

Oct. 7, 2004
“California professor wins Nobel Prize for chemistry”

Oct. 7, 2004



Irwin Rose, 78, who earned his B.S in 1948 and his Ph.D. in 1952 in biochemistry from the University of Chicago, will share the 2004 Nobel Prize for Chemistry with Aaron Ciechanover and Avram Hershko of Technion (Israel Institute of Technology), Haifa, Israel, "for the discovery of ubiquitin-mediated protein degradation," according to the press release from the Stockholm-based Nobel Foundation. Rose is now a professor emeritus of physiology and biophysics, at the College of Medicine, University of California, Irvine.

All three scientists will share this year's $1.36 million award.

At Chicago, Rose, known at the time as "Ernie," worked in professor Birgit Vennesland's laboratory, where he wrote his dissertation on the biochemical synthesis of nucleic acids.

After graduation, he spent most of his career at Fox Chase Cancer Center in Philadelphia.
Many of the studies that led to the Prize were done when Hershko and Ciechanover took sabbatical leave and worked with Rose in Philadelphia, the Foundation said in a statement.

The three researchers discovered one of the cell's most important cyclical processes, regulated protein degradation. All living things -- plants, animals and humans -- are built of proteins. In the late 1970s, biochemists knew a good deal about how the cell produces proteins. Rose, Ciechanover and Hershko "went against the stream," according to the press release, and discovered how cells break proteins down.

Beginning in 1978, they began to show that the cell functions as a "highly-efficient checking station where proteins are built up and broken down at a furious rate," according to the release. "The degradation is not indiscriminate but takes place through a process that is controlled in detail so that the proteins to be broken down at any given moment are given a molecular label, a 'kiss of death.'"

The labeled proteins are then funneled into proteasomes -- the cell's waste disposers -- large, cylindrical cellular machines that slice proteins into short pieces and thereby destroy them.

The researchers showed that the kiss-of-death label was a protein called ubiquitin, which cells tag onto doomed proteins. Once fastened onto a protein slated for destruction, the ubiquitin accompanies it to the proteasome, where it conveys the message that this protein has been selected for disassembly. Shortly before the protein is fed into the proteasome, its ubiquitin label is disconnected for re-use.

Thanks to the work of the three Laureates, "it is now possible to understand at a molecular level how the cell controls a number of central processes," the announcement continues, "by breaking down certain proteins and not others."

This research solved "a fundamental puzzle," said ubiquitin researcher Mark Hochstrasser, Ph.D., professor of molecular biophysics & biochemistry at Yale, who taught at the University of Chicago from 1990 to 2000. Before this, the process was completely obscure. The series of biochemical reactions discovered by Rose and colleagues was "both unprecedented and complex," he added. "It required someone who really knew enzymology."

Examples of processes governed by ubiquitin-mediated protein degradation include cell division, DNA repair, quality control of newly produced proteins, and regulation of the immune defense. More recently, evidence for at least a dozen similar systems has come to light.

When degradation does not work correctly, it can result in disease. Inflammation, cancer and neurodegenerative disease like Alzheimer's or Parkinson's disease are examples. Knowledge of ubiquitin-mediated protein degradation offers an opportunity to develop drugs against these diseases and others. The first such drug, known as Velcade (bortezomib), a proteasome inhibitor, was approved by the Food and Drug Administration in May 2003 to treat a type of cancer called multiple myeloma. Velcade blocks the activity of proteasomes, which can lead to death of cancer cells.

The ubiquitin-proteasome pathway, however, is involved in nearly every cellular process, points out Hochstrasser. "So you would expect a lot of side effects." The next step is to find more narrowly targeted interventions.

Is McKay, who we interviewed for GRC several years ago and was not one to use hype and had his doubts about the validity of some of the claims that were being made at the time,[particularly about stem cells and alzheimers] saying that the FOXA2 isn't differentiating dopamine neurons, which is causing them to spontaneously destruct? He also works with animals the right age compared to people who most often get PD as a model. If MPTP works just as well because we are getting it younger and younger, it sounds very hopeful that they have traced one cause, genetic biomarker, and a target.

I'll try to get the whole article. And yes Carey, the irony of the name is jumping off the page at me. Good thing he is experienced at feeling special, as I don't know if I could handle that one even with all of his experience. It's not the AliA2, or the RenoA2. He always says he's a lucky man and feels like he won the lottery. Maybe it was from all that time travel.

paula

Research Highlights, 1890 - 2007
1890 - Biological Laboratory at Cold Spring Harbor founded.

1908 - George Schull finds that by cross-pollinating corn plants, he can consistently produce higher yielding progeny. This theory of “hybrid vigor” has become widely known and has found many applications in agriculture and genetics.

1928 - E. Carleton MacDowell discovers a strain of mice predisposed to spontaneous leukemia. Subsequent breeding experiments lead to the development of mice with increased susceptibility or resistance to the cancer. This work laid the foundation of modern cancer research.

1930 - The first treatment for Addison’s disease - adrenal cortical hormone - is purified at Cold Spring Harbor Laboratory.

1945 - Milislav Demerec greatly increased wartime penicillin production by isolating a high yielding strain of the filamentous fungus Penicillium chrysogenum.

1951 - At the CSH Symposium, Barbara McClintock describes "controlling elements" which she found can switch other genes on and off as a consequence of their movement within the genome. In 1983, McClintock was awarded the Nobel Prize for her discoveries concerning controlling elements, commonly known as "jumping genes."

1952 - Alfred Hershey and Martha Chase carry out the classic "Waring blender" experiment which reinforced the idea that the genetic material is DNA, not protein.

1953 - James Watson gives the first public description of the newly-discovered DNA structure at the CSH Symposium. The discovery influences virtually all subsequent biological and medical research.

1962 - James Watson, Francis Crick, and Maurice Wilkins share the Nobel Prize for the discovery of the double helix structure of DNA.

1969 - Alfred Hershey is awarded the Nobel Prize for work he conducted on his own, with Martha Chase, and in collaboration with Max Delbrück and Salvador Luria (who received the prize along with Hershey).

1972 - Phil Sharp, William Sugden, and Joe Sambrook develop a technique for separating and visualizing DNA fragments that today is used worldwide.

1973 - Rich Roberts begins to purify large numbers of restriction enzymes, the molecular "scissors” that cut DNA at specific sequences. His group discovers many of the restriction enzymes used in recombinant DNA technology.

1977 - Rich Roberts, Louise Chow, Thomas Broker, and Richard Gelinas discover “split genes” in adenovirus. Roberts and Phil Sharp share the Nobel Prize in 1993 for their roles in this discovery.

1980 - Ronald McKay and Birgit Zipser develop monoclonal antibodies to study the nervous system of the leech.

1981 - Mike Wigler and his collaborators clone the first human, tumor-derived oncogene, H-ras. Wigler later identifies a key oncogenic (cancer-causing) mutation in H-ras and discovers that the distantly related budding yeast also has RAS genes.

1982 - Jim Hicks, Amar Klar, and Jeff Strathern determine the molecular mechanism of mating-type switching in yeast. Their results have important implications for understanding the complexities and dynamics of chromosome structure and gene regulation in many complex organisms.

1983 - Barbara McClintock is awarded the Nobel Prize for her discovery of mobile genetic elements ("jumping genes").

1988 - An important functional link between the two general classes of cancer causing genes (oncogenes and tumor-suppressor genes) is established by Ed Harlow and his colleagues. They show that the product of a viral oncogene acts by binding to the product of a tumor suppressor gene.

Winship Herr characterizes the POU domain, a conserved protein motif which defines a large family of transcription factors.

Late 1980s - David Beach and others begin to uncover the universal molecular events that control the cell cycle (how and when cells divide) in organisms ranging from yeast to humans.

1990 - Carol Greider clones a gene that encodes a component of an enzyme–telomerase–that maintains the integrity of the tips of chromosomes (telomeres).

1990s - David Beach and his colleagues begin to study the cell cycle in human cells, which leads to the discovery of many genes associated with human cancers.

1992 - Carol Greider, Bruce Futcher, and their colleagues show an association between telomere shortening and cell aging. This discovery suggests a possible reason for the unchecked proliferation of cancer cells.

Bruce Stillman and his colleagues purify a protein complex (ORC) that is required to trigger DNA replication in complex organisms including humans.

Robert Martienssen and colleagues devise a "gene-trap" system for the plant Arabidopsis that employs transposable elements.

1993 - Richard Roberts is awarded the Nobel Prize for his 1977 co-discovery of “split genes.” Roberts shares the Prize with former CSHL colleague Phil Sharp (who made the same discovery independently at MIT).

Mike Wigler and Nikolai Lisitsyn develop Representational Difference Analysis (RDA), a powerful tool for identifying mutations in cells with complex genomes.

1994 - Bruce Stillman and his colleagues complete a 10-year effort to reconstitute DNA replication with purified human-cell proteins.

Tim Tully, Jerry Yin, and Alcino Silva make key discoveries about the molecular basis of learning and memory in Drosophila and mice.

1996 - Scott Lowe and colleagues at Stanford University discover why certain tumors are resistant to chemotherapy.

W. Richard McCombie and Rob Martienssen establish the first global collaboration to sequence the entire genome of a flowering plant (Arabidopsis).

Yi Zhong discovers a role for the ras oncogene in learning and memory.
Former and future CSHL scientists Amar Klar and Shiv Grewal show that in some instances, the stable inheritance of genetic traits depends not only on DNA, but rather on DNA plus associated proteins.

1997 - Mike Wigler, Nick Tonks and their colleagues use RDA to identify the P-TEN tumor suppressor gene. They find that this gene is mutated in a large percentage of sporadic breast, prostate, and brain tumors.

1998 - After discovering "condensins" in 1997, Tatsuyana Hirano and his colleagues discover "cohesins." These related proteins modulate chromosome structure in preparation for cell division.

Yi Zhong discovers why defects in the NF1 gene cause both cancer and learning defects. This work is an important advance in understanding one of the most frequently inherited disorders affecting humans, neurofibromatosis.

1999 - Roberto Malinow and Karel Svoboda provide some of the first real-time, high-resolution images of the events that alter the number and strength of connections between neurons within an important site for learning and memory in the brain, the hippocampus.

Scott Lowe discovers why many human tumors are deficient in p53 tumor suppressor function despite the presence of normal p53 genes. This work has important implications for the proper diagnosis and treatment of cancer.

Dmitri Chklovskii develops a mathematical "wiring economy" principle that explains how neurons are positioned and connected in the brain so as to minimize the length - and hence the volume - of wiring between neurons.

2000 - Adrian Krainer and Michael Zhang discover why particular mutations in the BRCA1 gene predispose individuals to breast and ovarian cancer (the mutations disrupt "splicing enhancers").

Roberto Malinow obtains evidence that supports the use of benzodiazepines in the treatment of familial Alzheimer's disease.

W. Richard McCombie, Rob Martienssen and the Arabidopsis Genome initiative report the first complete genome sequence of a plant species.

Leemor Joshua-Tor, Arne Stenlund and their colleagues determine the shape and biochemical properties of a protein required for papillomavirus DNA replication. Papillomavirus infection is associated with virtually every case of human cervical cancer.

2001 - W. Richard McCombie, Lincoln Stein and their colleagues contribute to a landmark achievement in biological and biomedical research: the analysis of a >90% complete draft of the human genome.

2002 - Masaaki Hamaguchi and Michael Wigler discover the DBC2 tumor suppressor, a gene that is inactive in 60% of the most common forms of breast cancer, and is also altered in the majority of lung cancers.

Roberto Malinow obtains evidence that the dynamic replacement of AMPA receptors at synapses is likely to be a principle molecular mechanism of memory. In related studies, Malinow and Linda Van Aelst reveal the role of Ras and Rap proteins in controlling AMPA receptor trafficking.

2003 - Tim Tully and Josh Dubnau identify a large group of candidate memory genes that are potential targets for the development of therapies for treating human memory disorders.
Yi Zhong finds that expressing human Aß42 protein in the Drosophila brain is sufficient to trigger the plaque formation, nerve cell death, and memory loss associated with Alzheimer’s disease in humans.

CSHL scientists and their colleagues from some 20 genome research centers around the world publish the finished sequence and their initial analysis of the 3 billion letter human genome.

2004 - David Spector develops the first system for viewing how the "Central Dogma" of biology unfolds in its entirety, from DNA to RNA to protein, within living cells.

Scott Lowe and colleagues establish a promising combination therapy for treating many cancers that do not respond to traditional chemotherapy.

Gregory Hannon creates the first library of human RNA interference (RNAi) clones, which enables a wide variety of users to rapidly identify and validate target genes involved in disease.

2005 - Greg Hannon, Scott Lowe, and Scott Powers discover that “microRNAs” can play an important role in tumor progression and metastasis.

Alea Mills and her colleagues discover that the loss of a gene called p63 accelerates aging in mice. Similar versions of the gene are present in many organisms, including humans. The p63 gene is thus likely to play a fundamental role in aging.

Bioinformatics researcher Lincoln Stein and his colleagues in the International HapMap Consortium publish the first comprehensive collection of genetic variations in the world’s human population. This first version of the HapMap is already accelerating the search for genes involved in common diseases including cancer, heart disease, diabetes, asthma, and macular degeneration.

By determining the molecular structure of a protein that enables malaria parasites to invade human red blood cells, structural biologist Leemor Joshua-Tor uncovers valuable clues for rational anti-malarial drug design and vaccine development.

David Spector and his colleagues discover a new molecular mechanism that is likely to control the production of many proteins in humans and other organisms. A deeper understanding of this rapid response, "cut and run" mechanism is predicted to have broad implications for biology and biomedical research.

Carlos Brody develops a strikingly simple yet robust mathematical model of how short-term memory circuits are likely to store, process, and make rapid decisions about the information the brain receives from the world.

Dmitri Chklovskii discovers strongly preferred patterns of connectivity or “scaffolds” within the wiring diagram of the rat brain. The patterns are likely to correspond to modules that play an important role in brain function not only in rats, but also in humans.
Partha Mitra reveals an intriguing “one step back, two steps forward” effect of sleep on vocal learning in the zebra finch.

2006 – Scott Lowe, Michael Wigler, Greg Hannon, Robert Lucito, and Scott Powers identify two genes on chromosome 11 that are likely to have a role in liver cancer – the fifth most frequent neoplasm worldwide.

Marja Timmermans and colleagues show that the opposing activity of two small RNAs can control major developmental events in plants, establishing a paradigm likely to have broad implications for the biomedical sciences.

Zachary Mainen and colleagues are the first to show that neurons in the brain can integrate spatial and reward information.

2007 – Jonathan Sebat and Michael Wigler find a genetic distinction between sporadic and heritable forms of autism.

Adrian Krainer shows that the RNA splicing factor SF2/ASF can act as a cancer-causing protein by changing the alternative splicing of other genes critical for growth-control of cells.

Alea Mills identifies the protein, CHD5, as a master gene of a tumor suppressive network.
Scott Lowe and colleagues show that continuous inactivation of the p53 tumor suppressor pathway is required to maintain tumors in later stages of cancer.


http://www.cshl.edu/History/research.html

quote -
Researchers, however, have not yet cured any disease or even routinely turned embryo cells into specific adult cells. They got furthest in mice, where they converted mouse stem cells into brain cells like those lost in Parkinson's and into blood cells.

Dr. Ronald McKay, a stem cell researcher at the National Institute of Neurological Disorders and Stroke, counseled patience.

''We are essentially getting cells to differentiate without the rest of the embryo,'' Dr. McKay said. ''That has to be controlled and it has to be controlled in the lab. It's tricky stuff and it will take quite a while to figure out.''

''The problem is that everyone is looking for magic,'' Dr. McKay said. ''Academics are too.''

But, he said, to get to the next stage, when animals can routinely be cured of some diseases, like diabetes or Parkinson's, ''is likely going to take a new wave of technology or experiments.''