Possible Cause Of, and Treatment For, Non-Familial Parkinson’s

Feb. 6, 2013 — Columbia University Medical Center (CUMC) researchers have identified a protein trafficking defect within brain cells that may underlie common non-familial forms of Parkinson’s disease. The defect is at a point of convergence for the action of at least three different genes that had been implicated in prior studies of Parkinson’s disease. Whereas most molecular studies focus on mutations associated with rare familial forms of the disease, these findings relate directly to the common non-familial form of Parkinson’s.


 

The study was published today in the online edition of the journalNeuron.

The defective pathway is called the “retromer” pathway, in part because it can guide the reutilization of key molecules by moving them back from the cell surface to internal stores. In this study, defects in the retromer pathway also appear to have profound effects on the cell’s disposal machinery, which may explain why Parkinson’s disease brain cells ultimately accumulate large protein aggregates. The trafficking defects associated with Parkinson’s can be reversed by increasing retromer pathway activity, suggesting a possible therapeutic strategy. No current therapies for Parkinson’s alter the progression of the disease.

The researchers also found evidence that, even in unaffected individuals who simply carry common genetic variants associated with an increased risk of Parkinson’s disease, these molecular changes are at work. This supports the notion that early treatment approaches will be important in tackling Parkinson’s disease.

“Taken together, the findings suggest that drugs that target the retromer pathway could help prevent or treat Parkinson’s,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC.

In recent years, through genome-wide association studies (GWAS), researchers have identified about 10 common genetic variants that appear to have small effects on the risk of non-familial Parkinson’s, However, it has been hard to delve deeper into the impact of these variants. “When you look at patient brain tissue at autopsy, it’s usually too late — all the critical dopamine neurons are long gone and the damage has been done,” said Dr. Abeliovich.

In the current study, Dr. Abeliovich and his CUMC colleagues used an unusually broad array of approaches — including analyses of Parkinson’s disease-associated genetic variations, patient brain tissue, in vitro tissue culture studies of brain neurons, and fruit fly (Drosophila) models that harbor genetic variants related to those associated with Parkinson’s disease.

The researchers found that common variants in two genes previously linked to Parkinson’s disease, LRRK2 and RAB7L1, led to an unexpectedly similar impact on human brain tissue. The effects of the variants were found to be highly overlapping, pointing to a common pathway of action. Prominent cellular changes were observed in the retromer pathway, which is involved in the trafficking of proteins from the Golgi apparatus (which packages proteins for delivery to other cell components) to the lysosomes (which recycle proteins and other molecules). Mutations that affect the retromer pathway have also been found in familial Parkinson’s disease. Earlier studies from Columbia’s Taub Institute have shown that genetic variants in genes associated with retromer function are linked to Alzheimer’s disease and retromer component levels appear altered in Alzheimer’s disease brains, suggesting a broader role for retromer dysfunction in neurodegenerative diseases of aging, according to Dr. Abeliovich.

The impact of the RAB7L1 and LRRK2 variants was apparent even in individuals with no signs or symptoms of Parkinson’s disease. This suggests that there is a pre-disease state in unaffected carriers of the two genetic variants that favors early disease onset and that, in theory, could be targeted therapeutically.

The CUMC researchers also demonstrated that overexpression of one of the variants, RAB7L1, can overcome the effects of the other variant. Similarly, expression of VPS35, a gene involved in the retromer pathway, can suppress LRRK2 mutant pathology. “It will be interesting to look for drugs that directly target these retromer components or that more generally promote flow through the pathway,” said Dr. Abeliovich.

The title of the paper is “RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk.” The other contributors are David A. Macleod, Herve Rhinn, Tomoki Kuwahara, Ari Zolin, Gilbert Di Paolo, Brian D. McCabe, Lorraine N. Clark, and Scott A. Small, all at CUMC.

The study was supported by grants from the Michael J. Fox Foundation and the National Institutes of Health (NS064433, NS060876, NS060113, A6008702, AG025161, and AG08702-21.

 

Story Source:

The above story is reprinted from materials provided byColumbia University Medical Center.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Journal Reference:

  1. David A. MacLeod, Herve Rhinn, Tomoki Kuwahara, Ari Zolin, Gilbert Di Paolo, Brian D. MacCabe, Karen S. Marder, Lawrence S. Honig, Lorraine N. Clark, Scott A. Small, Asa Abeliovich. RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease RiskNeuron, 2013; 77 (3): 425 DOI:10.1016/j.neuron.2012.11.033
Columbia University Medical Center (2013, February 6). Possible cause of, and treatment for, non-familial Parkinson’s. ScienceDaily. Retrieved February 7, 2013, from http://www.sciencedaily.com/releases/2013/02/130206130946.htm

First Fruit Fly Model of Diet-Induced Type 2 Diabetes Shows How High-Sugar Diet Affects Heart; New Therapeutic Opportunities

Jan. 15, 2013 — Regularly consuming sucrose — the type of sugar found in many sweetened beverages — increases a person’s risk of heart disease. In a study published January 10 in the journal PLOS Genetics, researchers at Sanford-Burnham Medical Research Institute and Mount Sinai School of Medicine used fruit flies, a well-established model for human health and disease, to determine exactly how sucrose affects heart function. In addition, the researchers discovered that blocking this cellular mechanism prevents sucrose-related heart problems.

Cardiac fibrosis (shown in purple), a hallmark of heart disease, is clearly increased in fruit flies on a high-sugar diet (right), as compared to flies on a normal diet (left). (Credit: Image courtesy of Sanford-Burnham Medical Research Institute)

“Our study reveals a number of specific sugar-processing enzymes that could be targeted with therapies aimed at reducing sucrose’s unhealthy effects on the heart,” said Karen Ocorr, Ph.D., research assistant professor at Sanford-Burnham and the study’s corresponding author.

Diabetic fruit flies with heart problems

The research team was the first to model heart disease caused by type 2 diabetes in fruit flies. They achieved this simply by feeding the flies a diet high in sucrose. High-sucrose flies showed many classic signs of human type 2 diabetes, including high blood sugar and insulin signaling defects. The team also saw signs of diabetes-induced heart malfunction in these flies — deteriorating heart function, cardiac arrhythmia and fibrosis.

Next the researchers wanted to know exactly what sucrose is doing inside the flies’ cells that makes it harmful to hearts. To answer this question, they looked for molecular networks that are triggered or altered by sucrose.

The team eventually pinpointed one particular biochemical system, called the hexosamine pathway. This series of biochemical reactions normally plays only a minor role in the way cells process sugar to produce energy. But some research also suggests that the hexosamine pathway is linked to diabetes in humans.

“It’s remarkable that we’re able to use the fruit fly as a discovery tool for elucidating basic molecular mechanisms, not only of many types of heart disease, but also dietary influences that help us understand what happens in human hearts,” added Rolf Bodmer, Ph.D., professor at Sanford-Burnham and a senior author of the study.

Dampening sugar’s negative effect on the heart

The researchers further probed the hexosamine pathway in their new diabetes model. They found that artificially increasing sucrose-processing via the hexosamine pathway harms the heart. In contrast, when they specifically blocked this pathway, they prevented some of the high-sucrose induced heart defects, such as cardiac arrhythmias.

“Diet-induced heart damage is one of our society’s most serious health issues. Our flies now give us a tool to explore the role of high dietary sugar, and the means to identify treatments in the context of the whole body,” said Ross Cagan, Ph.D., professor at Mount Sinai School of Medicine and a senior author of this study.


Story Source:

The above story is reprinted from materials provided bySanford-Burnham Medical Research Institute. The original article was written by Heather Buschman.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Journal Reference:

  1. Jianbo Na, Laura Palanker Musselman, Jay Pendse, Thomas J. Baranski, Rolf Bodmer, Karen Ocorr, Ross Cagan. A Drosophila Model of High Sugar Diet-Induced CardiomyopathyPLoS Genetics, 2013; 9 (1): e1003175 DOI: 10.1371/journal.pgen.1003175
Sanford-Burnham Medical Research Institute (2013, January 15). First fruit fly model of diet-induced type 2 diabetes shows how high-sugar diet affects heart; New therapeutic opportunities. ScienceDaily. Retrieved January 27, 2013, from http://www.sciencedaily.com/releases/2013/01/130117084932.htm

Parkinson’s Treatment Can Trigger Creativity: Patients Treated With Dopamine-Enhancing Drugs Are Developing Artistic Talents, Doctor Says

Jan. 14, 2013 — Parkinson’s experts across the world have been reporting a remarkable phenomenon — many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.


 

Prof. Rivka Inzelberg of Tel Aviv University’s Sackler Faculty of Medicine first noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients — typically chocolates or similar gifts — took a surprising turn. “Instead, patients starting bringing us art they had made themselves,” she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor — all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report will be published in the journal Behavioral Neuroscience.

Giving in to artistic impulse

Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson’s patients is associated with tremors and a difficulty in coordinating their movements.

But it’s also involved in the brain’s “reward system” — the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It’s possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It’s possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.

Therapeutic value

Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.

The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. “We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative,” says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.

 

Story Source:

The above story is reprinted from materials provided byAmerican Friends of Tel Aviv University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


American Friends of Tel Aviv University (2013, January 14). Parkinson’s treatment can trigger creativity: Patients treated with dopamine-enhancing drugs are developing artistic talents, doctor says. ScienceDaily. Retrieved January 18, 2013, from http://www.sciencedaily.com/releases/2013/01/130114111622.htm

Artificial Butter Flavoring Ingredient Linked to Key Alzheimer’s Disease Process

ScienceDaily (Aug. 1, 2012) — A new study raises concern about chronic exposure of workers in industry to a food flavoring ingredient used to produce the distinctive buttery flavor and aroma of microwave popcorn, margarines, snack foods, candy, baked goods, pet foods and other products. It found evidence that the ingredient, diacetyl (DA), intensifies the damaging effects of an abnormal brain protein linked to Alzheimer’s disease.

Popcorn. A new study raises concern about chronic exposure of workers in industry to a food flavoring ingredient used to produce the distinctive buttery flavor and aroma of microwave popcorn, margarines, snack foods, candy, baked goods, pet foods and other products. (Credit: © alice / Fotolia)


 

The study appears in ACS’ journal Chemical Research in Toxicology.

Robert Vince and colleagues Swati More and Ashish Vartak explain that DA has been the focus of much research recently because it is linked to respiratory and other problems in workers at microwave popcorn and food-flavoring factories. DA gives microwave popcorn its distinctive buttery taste and aroma. DA also forms naturally in fermented beverages such as beer, and gives some chardonnay wines a buttery taste. Vince’s team realized that DA has an architecture similar to a substance that makes beta-amyloid proteins clump together in the brain — clumping being a hallmark of Alzheimer’s disease. So they tested whether DA also could clump those proteins.

DA did increase the level of beta-amyloid clumping. At real-world occupational exposure levels, DA also enhanced beta-amyloid’s toxic effects on nerve cells growing in the laboratory. Other lab experiments showed that DA easily penetrated the so-called “blood-brain barrier,” which keeps many harmful substances from entering the brain. DA also stopped a protective protein called glyoxalase I from safeguarding nerve cells. “In light of the chronic exposure of industry workers to DA, this study raises the troubling possibility of long-term neurological toxicity mediated by DA,” say the researchers.

The authors acknowledge funding from the Center for Drug Design (CDD) research endowment funds at the University of Minnesota, Minneapolis.

 

Link:

http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_ARTICLEMAIN&node_id=223&content_id=CNBP_030391&use_sec=true&sec_url_var=region1&__uuid=838f17b4-2326-4f81-9a9d-ccd12eb77ea4

Journal Reference:

  1. Swati S. More, Ashish P. Vartak, Robert Vince. The Butter Flavorant, Diacetyl, Exacerbates β-Amyloid Cytotoxicity. Chemical Research in Toxicology, 2012; : 120706140246003 DOI: 10.1021/tx3001016

Citation:

American Chemical Society (2012, August 1). Artificial butter flavoring ingredient linked to key Alzheimer’s disease process. ScienceDaily. Retrieved August 3, 2012, from http://www.sciencedaily.com­ /releases/2012/08/120801132606.htm

Skin Has an Internal Clock

ScienceDaily (July 19, 2012) — A research team at Charité – Universitätsmedizin Berlin together with scientists at a company in Hamburg has now discovered that human skin has an internal clock responsible for the time-based steering of its repair and regeneration, among other things.


 

The team published its first results from their basic research in the current issue of Proceedings of the National Academy of Sciences (PNAS).
Our skin is one of the body’s essential organs and perhaps the most versatile: Besides representative, communicative and sensory functions, it serves as our body’s boundary to the environment, forms an active and passive barrier against germs and helps keeping conditions constant for other important systems of the body, even though environmental conditions can change drastically. Frost, heat, sunlight and moisture — a variety of challenges for our skin — have different effects depending on the time of day.
Prof. Achim Kramer’s research team from the field of chronological biology at Charité and Dr. Thomas Blatt from the Skin Research Center in Hamburg have now found out that skin adapts to these time-dependent conditions.
The researchers took cell samples (keratinocytes) from the uppermost layer of skin from young, healthy test persons at various times of the day. Analysis of numerous genes in the keratinocytes showed that important factors for the regeneration and repair of skin cells are regulated by a biological clock. One of these factors, the molecule called the Krüppel-like-factor (Klf9) slows down cell division in the keratinocytes: When the researchers reduced the activity of this factor, they observed faster growth in the skin cell cultures. On the other hand, increased activity of Klf9 was connected with slower cell division. At the same time, it was shown that the stress hormone cortisol also controls the activity of Klf9 and can thus deploy a medical effect on common skin diseases like psoriasis.
The job of the biological clock is to control the exact timing of various processes like cell division, cell differentiation and DNA repair in skin. Prof. Kramer is already looking to the future: “If we understand these processes better, we could target the use of medication to the time of day in which they work best and have the fewest side effects.”

 

Journal Reference:

  1. F. Sporl, S. Korge, K. Jurchott, M. Wunderskirchner, K. Schellenberg, S. Heins, A. Specht, C. Stoll, R. Klemz, B. Maier, H. Wenck, A. Schrader, D. Kunz, T. Blatt, A. Kramer. Kruppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes. Proceedings of the National Academy of Sciences, 2012; 109 (27): 10903 DOI: 10.1073/pnas.1118641109

 

Charité – Universitätsmedizin Berlin (2012, July 19). Skin has an internal clock. ScienceDaily. Retrieved July 21, 2012, from http://www.sciencedaily.com­ /releases/2012/07/120719103608.htm