Link Between Pesticides and Parkinson’s Disease Identified

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Link Between Pesticides and Parkinson’s Disease Identified

Pesticides have long been thought to be involved in the pathology of PARKINSON’S DISEASE, but finding a definite link has been a near impossibility.  Many researchers spending many years of research sought to find this elusive relationship, and their primary theory has finally proven correct.  But it took some very advanced, newly developed technological research skills and two major teams of researchers to unlock the clues.

Past studies had shown there were increased risks to certain populations, such as farmers and others who were exposed to pesticides; however there were always people who never showed any response to their exposure.  Why were some folks more likely to develop PARKINSON’S DISEASE while others did not?  As the relatively new studies of genetics have advanced, the connection between genes and pesticides became clear.

Researchers at the Burnham Institute in La Jolla, California together with another team from the Whitehead Institute of the Massachusetts Institute of Technology in Cambridge, MA. used skin cells collected from people with PARKINSON’S DISEASE that carried the genetic mutation for alpha synuclein, the signature protein found in Lewy bodies.  From these skin cells, they induced human pluripotent stem cells to grow.  Pluripotent stem cells are able to develop into various specific types of cells when properly stimulated.  In the cells that they grew, they removed the genetic mutation for alpha synuclein in half of them and left it in the others.  They then programmed the cells to grow into the dopamine containing neurons found in PARKINSON’S DISEASE and began exposing both sets to various pesticides in varying amounts.

When they began to study the results of these exposures, the cells that carried the genetic mutation for alpha synuclein became damaged and cell death soon followed.  Those without the mutation survived.  So they started looking closer and found that in the cells with the genetic mutation, a vital mitochondrial pathway that protects cells with dopamine was interrupted, causing the cells to die.  In the non mutation carrying cells, this pathway would protect the cells and keep them alive and functional.

This study has shown beyond a doubt the relationship between the environment and a person’s genetics.  But while it has found one channel affecting dopamine neurons, this does not rule out that there may be many other mutations or pathways that could also be affected. Stuart Lipton, one of the lead researchers on this project says: “In the future, we anticipate using the knowledge of mutations that predispose an individual to these disease in order to predict who should avoid a particular environmental exposure.  Moreover, we will be able to screen for patients who may benefit from a specific therapy that can prevent, treat or possibly cure these diseases.”

Not being content merely to identify the problem, another principal investigator on this study decided to search for a solution to the problem.  Rajesh Ambasudhan explains:  “Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect…  One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides.”  This molecule is currently used in other drugs already approved by the Food and Drug Administration, so it may be possible to quickly find a way to repurpose these medications to provide an early treatment for Parkinson’s disease.

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Cell, November 27, 2013; NIH, P01 HD29587, P01 ES016738, and P30 NS076411, R37 CA084198

“Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1a transcription”

Cell, December 5, 2013.

Scott D. Ryan (1,*) Nima Dolatabadi (1,*), Shing Fai Chan (1), Xiaofei Zhang (1), Mohd Waseem Akhtar (1), James Parker (1), Frank Soldner (2), Carmen R. Sunico (1), Saumya Nagar (1), Maria Talantova (1), Brian Lee (1), Kevin Lopez (1), Anthony Nutter (1), Bing Shan (3), Elena Molokanova (1), Yaoyang Zhang (3), Xuemei Han (3), Tomohiro Nakamura (1), Eliezer Masliah (5), John R. Yates III (3), Nobuki Nakanishi (1), Aleksander Y. Andreyev (4), Shu-ichi Okamoto (1), Rudolf Jaenisch (2), Rajesh Ambasudhan (1), and Stuart A. Lipton (1,5).

 

Review by Marcia McCall

 

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One Mutated Gene Causes Multiple Neurodegenerative Disorders

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One Mutated Gene Causes Multiple Neurodegenerative Disorders

A single mutated gene targets cells in the basal ganglia and disrupts the cells’ abilities to function normally.  The gene, HPRT short for Hypoxanthine Guanine Phosphoribosyltransferase,, is considered a “housekeeping gene”, responsible for cellular maintenance and repair. When it is mutated, it affects the neurotransmitter dopamine and dopamine neurons and results in many neurological diseases including Alzheimer’s, PARKINSON’S DISEASE, Lesch-Nyhan, and Huntington’s disease.

Researchers on the study team lead by Theodore Friedmann, M.D., professor of pediatrics at the University of California, San Diego conducted a gene expression study using mouse embryonic stem cells modified to be lacking in HPRT. They found that when HPRT is deficient cells do not develop normally; although they appear as neurons, their functions are impaired.  Some of the impaired functions observed were with cell cycles and replication, RNA metabolism, DNA damage and repair as well as cell signaling.

Results of this study provide preliminary results, showing how a defect in this gene leads to the cellular defects found in many neurological diseases.  Research can now look for ways to target HPRT genetic mutation possibly leading to specific treatments.  It is one of many pathways in the development of neurological disease; the task of future research lies in finding ways to better understand these pathways.

Tae Hyuk Kang, Yongjin Park, Joel S. Bader, Theodore Friedmann. The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation.PLoS ONE, 2013; 8 (10): e74967 DOI:10.1371/journal.pone.0074967

 

reviewed by Marcia McCall

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Walking Speed and PARKINSON’S DISEASE

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Walking Speed and PARKINSON’S DISEASE

Researchers at the University of Michigan headed by Nicolaas Bohnen have found that the speed of walking in PARKINSON’S DISEASE depends not only on lack of dopamine but can also be affected by lack of acetylcholine.  This suggests that “the clinical heterogeneity of PARKINSON’S DISEASE results from variable involvement of different brain systems”, according to Dr. Bohnen.

In a study that involved 125 subjects with PARKINSON’S DISEASE, they found 38 of them lacked acetylcholine in addition to lack of dopamine.  When they compared the speed of walking to a control group of 32 non-Parkinsonian subjects, they found the group lacking dopamine walked only slightly slower than the control group.  The speed of the group lacking both acetylcholine and dopamine was markedly slower.

They also compared cognitive function in relation to speed of walking and found that the lack of acetylcholine “may reflect the impact of impaired cognitive processing during ambulation.”  The cognitive scores of subjects with lack of acetylcholine and dopamine were lower than those with lack of dopamine only, but non Parkinsonian subjects scored higher than both groups of subjects with PARKINSON’S DISEASE.

The results of this study indicate that people with PARKINSON’S DISEASE whose problems with walking speed do not improve on dopamine replacement therapy may have a form of PARKINSON’S DISEASE that is a multisystem neurodegenerative disorder.

Nicolaas I. Bohnen, MD, PhD, Kirk A. Frey, MD, PhD, Stephanie Studenski, MD, MPH, Vikas Kotagal, MD, Robert A. Koeppe, PhD, Peter J.H. Scott, PhD, Roger L. Albin, MD Martijn L.T.M. Müller, PhD;Gait speed in Parkinson disease correlates with cholinergic degeneration  Published online before print September 27, 2013, doi: 10.1212/WNL.0b013e3182a9f558Neurology 10.1212/WNL.0b013e3182a9f558

 

review by Marcia McCall

 

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Another Link in the Role of Alpha Synuclein in PARKINSON’S DISEASE

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Another Link in the Role of Alpha Synuclein in PARKINSON’S DISEASE

Travis Dunckley, Ph.D., an assistant professor and research scientist at the Translational Genomics Research Institute in Arizona has found that the absence of a particular protein, SMG1, may contribute to the accumulation of alpha synuclein in brain cells of people with PARKINSON’S DISEASE, various forms of dementia and multiple system atrophy.

SMG1 is a gene that helps cells in the manufacture and use of energy created in the mitochondria, the little power sources for each cell.  Dr. Dunckley and his team found that this protein was either very limited or lacking in post mortem brains of people with PARKINSON’S DISEASE and other neurodegenerative diseases.  To arrive at this discovery, they used very advanced genomic techniques to screen hundreds of human chemical regulators of cell function and cell metabolic processes to understand how they relate to the accumulation and aggregation of alpha synuclein. They found that lack of SMG1 was significantly related to the expression of synucleins in cells Knowledge of the specific actions or lack of action of these chemicals may lead to the development of specific drugs to prevent the development of alpha synuclein and its toxicity in brain cells.

The Mayo Clinic in Scottsdale, Arizona and the Banner Sun Health Institute, also in Arizona collaborated with Translational Genomics Research Institute and Dr. Dunckley on this study.  Their findings are published in the October 30, 2013 PLOS ONE journal.

 

Adrienne Henderson-Smith, Donald Chow, Bessie Meechoovet, Meraj Aziz, Sandra A. Jacobson, Holly A. Shill, Marwan N. Sabbagh, John N. Caviness, Charles H. Adler, Erika D. Driver-Dunckley, Thomas G. Beach, Hongwei Yin, Travis Dunckley. SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA ScreeningPLoS ONE, 2013; 8 (10): e77711 DOI: 10.1371/journal.pone.0077711

 

reviewed by Marcia McCall

 

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Falls and PARKINSON’S DISEASE

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Falls and PARKINSON’S DISEASE

As people age, falls become a more serious complication and people with PARKINSON’S DISEASE fall three times more often that people without.  Consequences of falls can range from minor bruising to fractures and loss of consciousness and account for many trips to the emergency room.  Some studies have shown that every third fall results in serious injury and after their fall, people begin to fear going out walking in public.

Several studies have focused on falls in PARKINSON’S DISEASE, most recently published are two papers by a Polish Research team who evaluated the causes and consequences of falls of people with PARKINSON’S DISEASE and looked at the risk factors for falls.  Their research found that sudden falls were the most common and were caused by problems related to PARKINSON’S DISEASE, such as freezing, postural instability, or sensory disturbances like vertigo.  Other research found that lack of arm movement lead to a higher risk of hip fractures and that stiffness and rigidity lead to falling backward.  They also found that subjects who were “multi-tasking” and thinking more about the task than their walking also had a higher incidence of falling.  Falls also occur during times when medications are not working properly.

There are many precautions that can be put in place to help make walking in the home safer and prevent falls.  Pay attention when in close quarters that require turning around or backing up, such as in bathrooms and kitchens, be extra aware.  The installation of grab bars in bathrooms can eliminate some of the problems, especially around showers, bathtubs and toilets.  Loose rugs in entryways are another hazard, they need to be smooth and firmly in place so they don’t slip or move around or else removed entirely for safety sake.  Long hallways can have hand rails installed the length of them to make waking easier.  Look at the arrangement of furniture, the backs of couches and sturdy chairs can serve as extra support for someone walking behind them; but some pieces of furniture, such as tables with sharp edges can be hazards to bump into and should be placed where they won’t cause a problem.  Going up and down stairs, whether they be a few or many, require sturdy handrails and step treads to be non-slip and perhaps even edged with reflective tape to make them more visible.  Good lighting in all areas is also a safety necessity.

Physical and occupational therapists can also help by showing people with PARKINSON’S DISEASE better ways to get up from chairs and from bed.  They can provide exercises to strengthen postural instability and improve gait and balance so walking becomes more natural and less hazardous.  People with PARKINSONS DISEASE need to be extra careful on standing up, especially since orthostatic hypotension (low blood pressure on standing) is a frequent problem.  Taking a moment to stretch and twist to improve blood flow before walking can also ensure a bit more safety from falling.  Following a regular exercise program to strengthen the spine and keep muscles in shape while improving posture is a good idea.

Use of a cane or a walker can also improve balance and is useful especially in crowded areas.  A cane or a walker can also signal to other people to stay out of the way and give a little more space to the person using it.  If there is a tendency to step or fall backward, a walker can be of use keeping the upper torso forward leaning and the movement going forward.

All falls should be reported to the neurologist, with a note about when and how they occurred.  It may be a simple tweaking of medication that can help prevent future falls, depending on when and how they happened.  Continuing physical therapy is also beneficial to keeping abreast of exercises and ways to prevent falls and remain independent as long as possible.

 

 

Marcia McCall

 

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February 2014 Conference

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      DO IT ALL with Parkinson’s!

doItAll

“A Fun Filled Day of Education & Empowerment”

FRIDAY, FEBRUARY 7, 2014

 

Registration & Continental Breakfast – 9:30am ● Program 10am – 3pm

PARKINSON PLACE 

5969 Cattleridge Blvd. • Suite 100 • Sarasota • FL • 34232 

Continental Breakfast & Lunch Provided 

$15 per personScholarships Available

Mark Your Calendar Today & Join Us for Great Topics & a Fun Way to Learn

AGENDA

 9:30am          CONTINENTAL BREAKFAST

   

  10:00am   SLEEP WELL – “Learn to Deal with Sleep Dysfunction”

                                    Patrick J. Madden, MD – Director, Neurology Clinic at Parkinson Place

 

  10:45am   STAY CONNECTED – “Learn to Live with Memory Loss

                          Pam Polowski – Certified Dementia Practitioner, Infinity Home Care

 

  11:30am   SPEAK UP – “Learn to Cope with Speech & Swallowing Problems”

           Mary Spremulli, MA, CCC-SLP – Speech Pathologist, Voice Aerobics™

 

 

  12:15pm                 LUNCH SERVED

 

 

  1:00pm    KEEP MOVING - “Learn to Benefit from Exercise & the Parkinson LSVT BIG Program”

                 Toya Crutchfield, PTRequest Physical Therapy at Parkinson Place

 

  1:45pm    EAT RIGHT – “Learn to Meet Your Nutritional Needs”

                  Bonni London MS, RD, LD/n, ACSM – Registered Dietician, London Wellness           

 

  2:30pm    LIGHTEN UP – “Learn to Give Up the Past, Engage in the Present & Hope for the Future”

                   Marilyn Tait – Parkinson Motivator & Advocate; PRF Executive Director

 

SPACE IS LIMITED RESERVATIONS REQUIRED  

TONI GOIN – 941.893.4188 ● TGoin@ParkinsonResearchFoundation.org

REGISTER ONLINE at http://www.eventbrite.com/e/do-it-all-with-parkinsons-tickets-9403210255

“Mushroom Alcohol”, Neurodegeneration and PARKINSON’S DISEASE

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“Mushroom Alcohol”, Neurodegeneration and PARKINSON’S DISEASE

During Hurricane Katrina, researcher Joan Bennett lived in New Orleans and worked at Tulane University.  Her home was flooded by the hurricane and during the clean up period, she was plagued with headaches, nausea and dizziness.  Her work was as a scientist, and specifically as a plant pathologist, so she collected samples of the molds she found wearing appropriate protective gear and masks and gloves. A bit later, she transferred her job to Rutgers.

There, she met Arati Inamdar, Ph.D., who is a researcher in the School of Environmental and Biological Sciences at Rutgers.  Together, they began testing Bennett’s samples of mold in hopes of finding why Bennett had been sickened after Katrina.  They discovered that those mold samples contained a volatile organic compound known as 1-octen-3-ol, that is also known commonly as mushroom alcohol.  They exposed fruit flies to this compound and found that they developed movement disorders similar to the disorders caused by pesticides such as rotenone or paraquat.  Further testing showed that 1-octen-3-ol caused loss of dopamine in two specific genes that lead to a loss of neurons and the development of Parkinson’s like symptoms.

“Parkinson’s has been linked to exposure to environmental toxins, but the toxins were man-made chemicals,” said Inamdar.  “In this paper, we show that biologic compounds have the potential to damage dopamine and cause Parkinson’s symptoms.”  Many new studies show that Parkinson’s disease is increasing in rural areas, but is often thought to be from exposure to pesticides.  Rural areas also have high rates of mold and mushroom exposure.  Now there is the possibility that for people with a genetic predisposition, molds and volatile compounds that are produced by molds and fungus may also lead to the development of symptoms like PARKINSON’S DISEASE.

As with most research projects, this work was accomplished by a team.  On this team were Muhammad Hossein, Jason Richardson, Alison Bernstein and Gary Miller.  Their paper was published this week in the journal Proceedings of the National Academy of Sciences..

 

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Arati A. Inamdar,Muhammad M. Hossain, Alison I. Bernstein, Gary W. Miller, Jason R. Richardson,and Joan Wennstrom Bennett PNAS 2013 ; published ahead of print November 11, 2013, doi:10.1073/pnas.1318830110

 

Review by Marcia McCall

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Pimavanserin Relieves Psychosis in PARKINSON’S DISEASE

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The result of a Phase III study that was released on November 1, 2013 demonstrated that Pimavanserin was effective in relieving symptoms of psychosis in people with PARKINSON’S DISEASE without worsening the other symptoms of the disease.  Pimavanserin is a new type of anti-psychotic drug that works by blocking the receptors for serotonin in areas of the brain that connect sensory perceptions and conscious thoughts.

Psychosis in people with PARKINSON’S DISEASE is not an uncommon occurrence.  It is a very serious issue that makes caregiving in the home nearly impossible and results in the admission of people with PARKINSON’S DISEASE to long term care facilities where they can be monitored day and night.  Prognosis is not good, and often marks the beginning of serious decline.

Hallucinations usually manifest as rather benign hallucinations, often of children or  seeing “little people”, but can sometimes be much more serious with visions of malevolent intruders or assume sexual overtones.  Long time use of anti-parkinson’s medications, such as levodopa replacement therapies is thought to be at least part of the cause as well as the disease pathology itself.  Sleep disturbances are also a major contributor to psychotic symptoms.  Newer studies have shown there are other irregularities in the white matter fibers of the brain that also contribute to psychoses in people with PARKINSON’S DISEASE, but whether the damage to white matter fibers is caused by the disease or contributes to the disease has not been clearly elucidated.

Neurologists’ usual response to hallucinations is to reduce levodopa to the lowest effective dose possible, and if that does not solve the problem, then to introduce antipsychotic medications.  Seroquel (quetiapine) is often the first drug of choice, but clinical trials have shown very limited benefit.  Clozaril is also a possible candidate, however it requires bi-weekly blood draws to monitor liver function, a major drawback for the already compromised lives of people with PARKINSON’S DISEASE.  Anti-depressants have sometimes shown good results, and certain anti cholinergic medications have also sometimes been effective, but side effects have been problematic.

Pimavanserin has been developed by the pharmaceutical company Acadia.  The Food and Drug Administration has agreed that the studies thus far conducted have been favorable and they are allowing Acadia to go forward with filing a New Drug Application.  A few more supportive studies must be undertaken before approval can be granted, but the company is focused on moving ahead to obtain FDA approval as quickly as possible.

 

News release from Acadia Pharmaceuticals

 

Article by Marcia McCall

 

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January 2014 Educational Conference

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PARKINSON RESEARCH FOUNDATION

Cordially Invites You to Attend Our

2014 Educational Conference for Patients, Caregivers & Community

BeYourBest

BE YOUR BEST

                                  With Parkinson’s!

FRIDAY, JANUARY 10, 2014 

Registration & Continental Breakfast: 9:30am ● Program: 10am-2pm

 

PARKINSON PLACE

5969 Cattleridge Blvd., Suite 100, Sarasota, FL. 34232

Continental Breakfast & Lunch Provided

$15 per person ● Scholarships Available

Agenda

“Overview of Parkinson’s Disease and Newer Drugs in the Pipeline”

Juan Sanchez-Ramos, MD, PhD – Fellowship Trained Movement Disorders Specialist
Director, USF Parkinson Clinic at Parkinson Place, PRF Medical Director

 

“Non-Motor Symptoms of Parkinson’s Disease: Cognition and Behavior”

Patrick J. Madden, MD – Director, Neurology Clinic at Parkinson Place

 

“Stem Cell Treatment for Parkinson’s Disease”

James M. Schumacher, MD – Neuroregeneration Institute, Harvard Medical School

 

“Three Steps to a Better Life with Parkinson’s”

Marilyn J. Tait – Parkinson Educator, Motivator & Advocate; PRF Executive Director

SPACE IS LIMITED ● RESERVATIONS REQUIRED

TONI GOIN – 941.893.4188 – TGoin@ParkinsonResearchFoundation.org

 

PREPAY FOR TICKETS ONLINE

https://www.eventbrite.com/e/be-your-best-with-parkinsons-tickets-9395776019

                        ParkinsonResearchFoundation.org

Two Forms of Alpha-Synuclein; Two Forms of PARKINSON’S DISEASE

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Two different laboratories of researchers, one in France and one in the U.S. have found that alpha-synuclein, while the same biologically and molecularly, can form two distinct types of forms or strains, which perhaps explains why people with PARKINSON’S DISEASE experience such different symptoms.

The French team from the Laboratoire CNRS d’Enzymologie et Biochime Structurales published their paper on October 10 in the Journal Nature Communications.  This team identified two distinct shapes for the aggregates of alpha synuclein, one is round, “spaghetti” like and the other is flat, “linguini” like.  The spaghetti shape is much more toxic, rapidly penetrating and ultimately killing the cells in the brain.  It is very resistant to cell chemistry that would normally be able to eliminate unwanted intruders, such as viruses or other destructive proteins.  Linguini forms on the other hand, are more easily controlled by the cell and become toxic to the cell much more slowly.

This team thinks that the differences in the shapes of the aggregates may be responsible for the differences in the symptoms of PARKINSON’S DISEASE between those that are primarily motor affected, such as tremor, and those that are cognitive or behavioral.  While they are continuing to refine their research and better characterize the structures of alpha-synuclein, they believe that this process could lead to a targeted therapeutic treatment specific to each strain.

In the US, a team led by Virginia Lee and John Q. Trojanowski, two esteemed researchers in PARKINSON’S DISEASE from the Perelman School of Medicine at the University of Pennsylvania,  have discovered that alpha-synuclein can take on two different forms despite having the same chemical make up and interact with other disease proteins found in Alzheimer’s, PARKINSON’S and other neurodegenerative disease.

Tau protein is a marker of Alzheimer’s and alpha-synuclein is a marker for PARKINSON’S.  Post mortem brains of people with PARKINSON’S who had symptoms of cognitive decline or dementia showed both tau and alpha-synuclein closely entwined. Brains of patients that did not have dementia also has aggregates of alpha-synuclein, but the shape of the protein was different.  This could correspond to the “spaghetti” and “linguini” models.  However, Lee and Trojanowski found that over time, this strain  could change into the more fibril type found with the dementia, but it took longer for it to become entangled with tau. They speculate that these different shapes assumed by alpha-synuclein may be responsible for the different symptoms observed in different PARKINSON’S DISEASE patients, why some patients have more motor symptoms and others are affected with more cognitive decline or dementia.

More research is needed to validate and explore these findings more clearly.  But it also could lead to more therapeutic targets for treatment.  If each strain can be clearly defined, it can be selectively targeted by antibodies designed specifically for each strain.  Lee says “What we’ve found opens up new areas for developing therapies and particularly immunotherapies for PARKINSON’S and other neurodegenerative diseases.”

 

 

 

Luc Bousset, Laura Pieri, Gemma Ruiz-Arlandis, Julia Gath, Poul Henning Jensen, + et al. Structural and functional characterization of two alpha-synuclein strains  Nature Communications 4, doi:10.1038/ncomms3575

Jing L. Guo, Dustin J. Covell, Joshua P. Daniels, Michiyo Iba, Anna Stieber, Bin Zhang, Dawn M. Riddle, Linda K. Kwong, Yan Xu, John Q. Trojanowski, Virginia M.Y. Lee  Distinct α-Synuclein Strains Differentially Promote Tau Inclusions in Neurons Cell: 3July2013; 154:1

 

Review by Marcia McCall

 

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