[Stitcher]

UCLA Find Yields Further Insight into Causes of Parkinson's Disease

FOR IMMEDIATE RELEASE
Wednesday, January 31, 2007
University of California Los Angeles
http://ucnewswire.org/news_viewer.cf...93F7D488749C19

In humans, a dearth of the neurotransmitter dopamine has long been known to play a role in Parkinson's disease. It is also known that mutations in a protein called parkin cause a form of Parkinson's that is inherited.

Now, UCLA scientists, reporting in the Jan. 31 issue of The Journal of Neuroscience, have put the two together. Using a new model of Parkinson's disease they developed in the simple Drosophila (fruit fly), the researchers show for the first time that a mutated form of the human parkin gene inserted into Drosophila specifically results in the death of dopaminergic cells, ultimately resulting in Parkinson's-like motor dysfunction in the fly. Thus, the interaction of mutant parkin with dopamine may be key to understanding the cause of familial Parkinson's disease - Parkinson's that runs in families.

Conventional wisdom has held that parkin is recessive, meaning that two copies of the mutated gene were required in order to see the clinical signs of Parkinson's disease. But the researchers, led by George Jackson, M.D., Ph.D., UCLA associate professor of neurology and senior scientist at the Semel Institute for Neuroscience and Human Behavior at UCLA, wanted to see if they could get the protein to act in a dominant fashion, so they put only one copy of the mutation into their fly model. The result was the death of the neurons that use dopamine, the neurotransmitter long implicated in Parkinson's disease.

"We put the mutant parkin in all different kinds of tissues and in different kinds of neurons, and it was toxic only to the ones that used dopamine," Jackson said. "No one's shown this degree of specificity for dopaminergic neurons."

Having a genetic model of Parkinson's disease (PD) in the fruit fly will allow researchers to run mass testing, or "screens," of genes in order to find the novel pathways - networks of interacting proteins that carry out biological functions - that control survival of those dopaminergic neurons.

"Since a lot of those pathways regulating cell survival and death are conserved by evolution all the way from flies to humans," said Jackson, "if we find those genes in the fly, they may represent new therapeutic targets for PD in humans."

The researchers examined the results not only from a genetic standpoint but from a behavioral standpoint as well. To measure the progression of Parkinson's disease in the fly, they designed a small series of rotating glass cylinders that they christened a "fly rotarod." A healthy fly placed inside the hollow cylinder would simply cling to the wall during the slow 360-degree loop. But flies with Parkinson's disease would fall, depending on the progression of their disease. The researchers used infrared beams to measure when they fell.

The researchers also plan to use their fly model to test a library of some 5,000 drug compounds approved by the Food and Drug Administration to see which ones might stop disease progression. If they find one that works, such a compound, which could serve as a kind of skeleton for other therapeutic drugs, could then be tested in mouse models and eventually in humans.

While non-scientists may have trouble understanding how a simple fruit fly can have implications for humans, Jackson said that, thanks to the biological similarities between species, "the point of what we do is that if we find things, then ultimately, we can examine them in humans."

Besides Jackson, other UCLA investigators included Tzu-Kang Sang, Hui-Yun Chang, George M. Lawless, Anuradha Ratnaparkhi, Lisa Mee, Larry C. Ackerson, Nigel T. Maidment and study co-author David E. Krantz.

The UCLA Department of Neurology encompasses more than a dozen research, clinical and teaching programs. The department ranked No. 1 among its peers nationwide in National Institutes of Health funding in 2005. For information, visit http://neurology.medsch.ucla.edu.

The Semel Institute for Neuroscience and Human Behavior at UCLA is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders. For information, visit http://www.npi.ucla.edu.

-UCLA-
MW058

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Additional Resources:
Mark Wheeler
UCLA
(310) 794-2265
mwheeler@mednet.ucla.edu

[olsen]

one of the first movement disorder speicalist my husband consulted (she retired before his 6 month check up) maintained that until there was an animal model for parkinson's there would not be much progress in "real" treatments. do flies constitute a reasonable model i wonder???

[ashleyk]

FYI. This paper is difficult for me to understand but the general thought is that neuro-inflamation is the cause of PD. And there may be drug therapies available now (like opioid antagonists, LDN) used with early PET scans to stop progression. Dr. Hong from the NIH has published papers on this subject.
Ashley

http://www.nature.com/nrn/journal/v8...l/nrn2038.html
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

Michelle L. Block1, Luigi Zecca2 and Jau-Shyong Hong1 About the authors
Top of page
Abstract

Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.

* View At a Glance

For many years, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease have been a major focus of neuroscience research, with much effort being devoted to understanding the cellular changes that underlie their pathology. Microglia, the resident innate immune cells in the brain, have been implicated as active contributors to neuron damage in neurodegenerative diseases, in which the overactivation and dysregulation of microglia might result in disastrous and progressive neurotoxic consequences. Although these concepts have been widely reviewed in recent years1, 2, 3, the characteristics defining deleterious microglial activation and the mechanisms by which neurotoxic microglial activation is initiated remain poorly understood. In the current review, we therefore focus on recent reports indicating that pattern recognition receptors (PRRs) are tools used by microglia to identify neurotoxic stimuli and that stimulation of NADPH oxidase activity is the predominant mechanism through which microglia produce neurotoxic reactive oxygen species (ROS). We further explain how the identification of these crucial participants in microglia-mediated neuronal injury could provide the insight necessary for the development of novel markers that specifically define deleterious microglial activation. Furthermore, these mechanisms might be ideal prospects for targeted anti-inflammatory therapy capable of slowing and perhaps preventing neurodegenerative diseases.

In summary, inflammation-mediated neurotoxicity in neurodegenerative disease can occur as a consequence of microglial dysregulation and overactivation. Microglia monitor the brain environment by interpreting and processing stimuli (environmental toxins, endogenous proteins or reactive microgliosis) through PRRs. Several of these factors might be correctly recognized by microglia as pathogenic. However, misinterpretation of innocuous stimuli through PRRs could be a predominant mechanism through which microglia become overactivated and uncontrolled, and therefore able to exert neurotoxic effects. Although different combinations of receptors might be involved in the recognition of toxic and pro-inflammatory stimuli, there is a common deleterious downstream pathway, involving oxidative stress that both induces neuronal death and amplifies ongoing microglial activation to drive perpetuating neurotoxicity. Given the progressive and cumulative contribution of microglial activation throughout the course of neurodegenerative diseases, imaging microglia might be useful for the early identification of neurodegenerative disease. Monitoring of microglial activation throughout the disease would give an indication of when to begin anti-inflammatory treatment capable of altering disease progression, and provide feedback that allows an individually tailored therapeutic regimen based on response to therapy. Future research will need to focus on detailing the mechanisms responsible for microglial overactivation in an effort to identify more specific markers for in vivo imaging and provide the basis for the development of compounds that have greater therapeutic efficacy.