Alzheimer's, Parkinson's, ALS: Scientists reveal structural secrets of nature's little locomotive

A team led by scientists at The Scripps Research Institute has determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells. The complex's large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

Credit: Image courtesy of the Lander lab, The Scripps Research Institute.

Date:

March 9, 2015

Source:

Scripps Research Institute

Summary:

Scientists have determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells. The complex's large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

A team led by scientists at The Scripps Research Institute (TSRI) has determined

the basic structural organization of a molecular motor that hauls cargoes and 

performs other critical functions within cells.

Biologists have long wanted to know how this molecular motor -- called the 

"dynein-dynactin complex" -- works. But the complex's large size, myriad 

subunits and high flexibility have until now restricted structural studies to small 

pieces of the whole.

In the new research, however, TSRI biologist Gabriel C. Lander and his 

laboratory, in collaboration with Trina A. Schroer and her group at Johns Hopkins 

University, created a picture of the whole dynein-dynactin structure.

"This work gives us critical insights into the regulation of the dynein motor and

 establishes a structural framework for understanding why defects in this system

 have been linked to diseases such as Huntington's, Parkinson's, and

 Alzheimer's," said Lander.

The findings are reported in a Nature Structural & Molecular Biology advance

online publication on March 9, 2015.

Unprecedented Detail

The proteins dynein and dynactin normally work together on microtubules for 

cellular activities such as cell division and intracellular transport of critical cargo

 such as mitochondria and mRNA. The complex also plays a key role in neuronal 

development and repair, and problems with the dynein-dynactin motor system 

have been found in brain diseases including Alzheimer's, Parkinson's and

 Huntington's diseases, and amyotrophic lateral sclerosis (ALS). In addition,

 some viruses (including herpes, rabies and HIV) appear to hijack the dynein-

dynactin transport system to get deep inside cells.

"Understanding how dynein and dynactin interact and work, and how they 

actually look, is definitely going to have medical relevance," said Research

 Associate Saikat Chowdhury, a member of the Lander lab who was first author of 

the study.

To study the dynein-dynactin complex, Schroer's laboratory first produced 

individual dynein and dynactin proteins, which are themselves complicated, with

 multiple subunits, but have been so highly conserved by evolution that they are 

found in almost identical form in organisms from yeast to mammals.

Chowdhury and Lander then used electron microscopy (EM) and cutting-edge 

image-processing techniques to develop two-dimensional "snapshots" of dynein's

 and dynactin's basic structures. These structural data contained unprecedented

 detail and revealed subunits never observed before.

Chowdhury and Lander next developed a novel strategy to purify and image 

dynein and dynactin in complex together on a microtubule -- a railway-like

 structure, ubiquitous in cells, along which dynein-dynactin moves its cargoes.

"This is the first snapshot of how the whole dynein-dynactin complex looks and 

how it is oriented on the microtubule," Chowdhury said.

Pushing the Limits

The structural data clarify how dynein and dynactin fit together on a microtubule,

 how they recruit cargoes and how they manage to move those cargoes

 consistently in a single direction.

Lander and Chowdhury now hope to build on the findings by producing a higher-

resolution, three-dimensional image of the dynein-dynactin-microtubule complex, 

using an EM-related technique called electron tomography.

"The EM facility at TSRI is the best place in the world to push the limits of

 imaging complicated molecular machines like these," said Lander.

The research was supported by the Damon Runyon Cancer Research Foundation 

(DFS-#07-13), the Pew Scholars program, the Searle Scholars program and the

 National Institutes of Health (DP2 EB020402-01, GM44589).

Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.

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Journal Reference:

1. Saikat Chowdhury, Stephanie A Ketcham, Trina A Schroer, Gabriel C Lander. Structural organization of the dynein–dynactin complex bound to microtubules. Nature Structural & Molecular Biology, 2015; DOI: 10.1038/nsmb.2996

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Scripps Research Institute. "Alzheimer's, Parkinson's, ALS: Scientists reveal structural secrets of nature's little locomotive." ScienceDaily. ScienceDaily, 9 March 2015. <www.sciencedaily.com/releases/2015/03/150309160614.htm>.

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Sage Bionetworks and The Michael J. Fox Foundation Collaborate to Amplify Parkinson’s Patient Voice in Research

March 09,2015

• Parkinson mPower iPhone app-based clinical study provides intuitive platform for empowering research participants as partners to illuminate Parkinson’s disease symptom variation
• mPower uses ResearchKit, a new software framework announced today by Apple that turns iPhone into a powerful tool for medical research
• Fox Insight virtual clinical study offers every Parkinson’s patient the opportunity to securely contribute data to speed the cure

Sage Bionetworks, a nonprofit biomedical research organization, in collaboration with The Michael J. Fox Foundation for Parkinson’s Research (MJFF) today announced the launch of Parkinson mPower (mPower), a patient-centered, iPhone app-based study of symptom variation in Parkinson’s disease.

mPower (Mobile Parkinson Observatory for Worldwide, Evidence-based Research) uses the new ResearchKit software framework announced today by Apple to make it easy for people with Parkinson’s disease to contribute data to researchers investigating symptom variation. ResearchKit turns iPhone into a powerful tool for medical research by enabling participants to complete tasks or submit surveys right from the mPower app. This new software framework delivers a simple way to present study participants with an interactive informed consent process, which helps explain the study's purpose, how data will be used and the app's privacy policy.

MJFF also announced the launch of Fox Insight, a Web-based virtual clinical study open to individuals of any age, both with and without Parkinson’s disease, worldwide. Later this year, data collected from participants who enroll in both mPower and Fox Insight will be used to validate the power of these two approaches in accelerating Parkinson’s disease research.

“MJFF recognizes patients and their families and loved ones as vital partners in Parkinson’s research,” said Todd Sherer, PhD, chief executive officer of MJFF. “Technologies such as ResearchKit, in combination with the mPower app and Fox Insight study, expand the opportunity for these key stakeholders to propel research forward by contributing data from their daily experience.”

mPower: App-Based Study of Parkinson’s Disease Variation

mPower is a unique, iPhone app-based study developed in collaboration with Ray Dorsey, MD, at the University of Rochester and Max Little, PhD, at Aston University, United Kingdom. By combining surveys and tasks that make use of iPhone sensors to collect data on abilities affected by Parkinson’s disease, including dexterity, balance/gait, and certain vocal characteristics, mPower aims to offer insight into the variability of Parkinson’s. The study will also highlight how mobile devices and sensors can help measure the disease and its progression, advancing research and care practices and ultimately helping to improve quality of life for people with Parkinson’s.

“Researchers who have made the effort to work together in the kinds of communities enabled by Sage’s platforms are becoming massively more productive,” said Stephen Friend, MD, PhD, president of Sage Bionetworks and mPower principal investigator. “But we need more data. In a traditional clinical study, you’d be thrilled to find 500 research ‘subjects.’ But imagine what is possible when you can quickly and reliably activate 20,000 research ‘partners.’ More importantly, participants need to be equal partners and be able to track changes in their own symptoms. It is through sharing insights and data among patients and researchers that we all find ‘windows of intervention.’”

mPower will collect real-time, objective data through a series of well-validated tasks. The app will remind users to complete the tasks before and after taking medication, and at the end of each day. The study also will collect additional patient-reported data, such as from wearable devices and surveys.

“We know that Parkinson’s disease symptoms fluctuate over the course of a day, or a week, but that has never been measured objectively,” said Dorsey, co-director of the Center for Human Experimental Therapeutics at the University of Rochester Medical Center. “The mPower study will enable us to learn from patients, and we’ll be able to give information back to patients so they can manage their conditions regardless of where they live and regardless of their mobility.”

Sage Bionetworks is a strong proponent of open-source innovation. As such, participants in the mPower study can choose to make their data available for future studies conducted by researchers worldwide.

In addition to Dorsey and Little, Sage Bionetworks, led by senior physician Andrew Trister, MD, PhD, was advised in development of mPower by Karl Kieburtz, MD, MPH, at the University of Rochester, Caroline Tanner, MD, PhD, at the University of California San Francisco, and Bas Bloem, MD, PhD, at Radboud University Medical Centre in Nijmegen, the Netherlands.

mPower is available for download today on the App Store. The mPower study is open to all U.S. residents over age 18, regardless of a diagnosis of Parkinson’s disease.

Fox Insight: The Patient Experience Fueling Research

Fox Insight (foxinsight.org) is a virtual clinical study aiming to gather an unprecedented dataset and provide research with a holistic view of the lived experience of Parkinson’s disease. Fox Insight seeks to collect user-generated data gathered initially through surveys and “virtual clinic visits.” Over time, the site will evolve to work in concert with apps such as mPower, wearable computing, and other emerging technologies for increasingly passive and non-burdensome data collection from patients and control volunteers around the world. The study is open to any Parkinson’s patient with a computer and access to the Internet, as well as to individuals who do not have Parkinson’s disease.

The goal is to capture and analyze clinical data that can contribute to broader understanding of Parkinson’s, help establish reliable outcome measures for drug development, replace outdated clinical patient assessments and accumulate critical masses of data large enough to reveal previously undetectable aspects of PD and open up new avenues of PD research.

Core to the MJFF philosophy, all data collected through Fox Insight will be de-identified and made available to researchers worldwide for independent studies. Making this data available to the research community at large can rapidly accelerate progress by reducing cost and effort spent across individual projects and promoting replicable results.

mPower/Fox Insight 2015 Combined Study

Later in 2015, MJFF and Sage Bionetworks, along with Sage’s mPower collaborators, will jointly conduct a study of participants contributing data through both mPower and the Fox Insight platform. The combined study aims to amplify the voice of Parkinson’s patients and elevate their role as partners in research.

mPower participants with a diagnosis of Parkinson’s disease will be given the opportunity to consent to provide their data to the combined study. Additionally, MJFF will make Fox Insight users aware of the opportunity to download the mPower app and participate in the combined study.

Pending results of the combined study, MJFF will further develop and customize mPower to leverage the potential synergies of the mPower mobile app study platform and the Fox Insight platform.

A Commitment to Developing Emerging Technologies for Patient Benefit

Sage Bionetworks works to redefine how complex biological data is gathered, shared and analyzed. Through Sage’s efforts, patients and researchers become partners and together accelerate discoveries for patient benefit.

The Michael J. Fox Foundation is committed to developing emerging technologies for the benefit of Parkinson’s patients. In August 2014, the Foundation announced a collaboration with Intel Corporation to develop big data analytics and wearable technologies to speed Parkinson’s drug development. This ongoing effort is an important step in enabling researchers and physicians to measure progression of the disease and to speed progress toward breakthroughs in drug development.

About The Michael J. Fox Foundation for Parkinson’s Research

As the world’s largest nonprofit funder of Parkinson’s research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson’s disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson’s patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding more than $450 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson’s research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson’s disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson’s awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world.

About Sage Bionetworks

Sage Bionetworks is a 501(c)(3) nonprofit biomedical research organization, founded in 2009, with a vision to promote innovations in personalized medicine by enabling a community-based approach to scientific inquiries and discoveries. Sage Bionetworks strives to activate patients and to incentivize scientists, funders and researchers to work in fundamentally new ways in order to shape research, accelerate access to knowledge and transform human health. It is located on the campus of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and is supported through a portfolio of philanthropic donations, competitive research grants, and commercial partnerships. More information is available at http://www.sagebase.org.

EXCLUSIVE: Parkinson's link to statins: Calls to end widespread use of the drug

PLANS for the mass prescription of statins should be shelved after a study linked the drug to Parkinson’s disease, an expert last night warned.

Published: 08:43, Sun, March 8, 2015

By LUCY JOHNSTON

OVOLABS_4 END

statins

Dr Kailash Chand, deputy chairman of the British Medical Association, was speaking following research which found those who take the cholesterol-lowering drugs are more than twice as likely to develop Parkinson’s disease in later life than those who do not.

A study last week showed statin use increases the risk of diabetes by 46 per cent.

It has led to calls to end to the widespread use of the drugs.

The risks of side-effects of these drugs are far greater than any potential benefits and it is high time these drugs were restricted in the low-risk population

Dr Kailash Chand

The Parkinson’s research carried out over 20 years, and involving nearly 16,000 people, suggests cholesterol may have a vital role in protecting the brain and nervous system.

The findings have alarmed experts who say if applied to the number of Britons deemed eligible for statins it could equate to 150,000 extra patients with Parkinson’s, a central nervous system disorder affecting one in 350 mostly older people.

The work has also fuelled concerns that statins, now recommended for up to half the adult population over 50 by government drug policy adviser the National Institute for Health and Care Excellence, may be doing many patients more harm than good.

Doctors used to prescribe the drugs only to those who had a 30 per cent or greater risk of suffering a heart attack within a decade, but this was lowered to 20 per cent in 2005.

A 10-year plan has been introduced to reduce this further and include low-risk patients who have just a 10 per cent chance of a heart attack within a decade.

Nice believes this could save thousands of lives.

Other studies have shown a link between the cholesterol-lowering drugs and potentially disabling side effects including cataracts, diabetes, muscle pains, fatigue and memory loss.

Researchers warn that the mass roll-out of statins leaves 150,000 people at risk

Dr Chand, who suffered debilitating muscle pains while taking statins, said of the Parkinson’s research: “This research has been done over a considerable amount of time and on a considerable number of people and it is very worrying.”

Speaking in a personal capacity, he added: “The risks of side-effects of these drugs are far greater than any potential benefits and it is high time these drugs were restricted in the low-risk population and only given to people with existing heart disease.”

Dr Xuemei Huang, who led the research on the link with Parkinson’s disease, recently published in the journal of Movement Disorders, expressed concerns about the widespread prescription of statins.

The professor of neurology at Penn State College of Medicine in Pennsylvania said: “If we blanket prescribe statins to people we could be creating a huge population of people with neurological problems.

“Does mother nature create cholesterol for a reason?

"I think doctors are over-enamoured with statins and think it is a cure-all.

“But the body is not just for the heart, it is also for the brain.

"It is potentially harmful for these drugs to be given out so widely and randomly.”

Last year leading doctors’ magazine Pulse revealed two-thirds of GPs are disregarding Nice advice to offer statins to more patients. 

Related articles

•          How statins can cause diabetes: Pills raise the risk of getting disease by 46 per cent
•          Cholesterol and death certificates: Doctor Rosemary Leonard answers your medical  queries
•          EXCLUSIVE: Statins expert calls for safety checks over the drug

http://www.express.co.uk/life-style/health/562600/Parkinsons-link-statins-mass-use-drug-risk-thousands-developing-nerve-disease

Rocking Out with Parkinson's

FoxFeed Blog

Posted by  Pat Torpey, March 02, 2015

Longtime professional drummer Pat Torpey shares his experience with Parkinson’s disease and how his bandmates and family stand by his side as he continues touring the world.

March 6 is my wife’s birthday. It’s also the day, in 2014, that I was diagnosed with Parkinson’s disease. Not exactly the kind of news you want hear on any day, let alone a joyous occasion.

As I sat in my doctor’s office, I saw his mouth move, but didn’t hear what he was saying. My mind raced as I thought of my amazing 11-year-old son and my beautiful wife, Karen. I was afraid of how this would affect our life and marriage. I thought of the drums and was afraid that I'd never be able to play again.

But I'm getting ahead of myself.

I've been a professional musician — a drummer — for over 30 years. I've played on "American Bandstand" and "The Tonight Show." I've toured with Led Zeppelin vocalist Robert Plant, the Knack and Belinda Carlisle and recorded with many other artists. I’m also a founding member of the band Mr. Big. We were lucky enough to have a No. 1 hit in the U.S. and 15 other countries in 1992 with a song called "To Be With You."

I’ve always led a clean life, kept myself in good physical and mental condition, ate well and stayed active, and avoided the pitfalls that sometimes come with a career in rock and roll.

But in spring of 2008 I noticed something “strange” in my right foot and the way it moved when I played. I tried everything to fix the problem: used different pedals, shoes, drumheads, but nothing helped. I was originally diagnosed with essential tremor, until 2014 when my symptoms intensified. I began experiencing waves of fatigue, loss of appetite and eventually had trouble playing just one song, let alone a full two hour concert.

My wife urged me to go to the doctor again and that’s when I got the diagnosis. Following this moment, I fell into a deep depression. This was all new to me.

Meanwhile, there was a new Mr. Big album that needed to be finished and a tour in the planning stages. I couldn't see myself doing either. I called a meeting and told the band to get another drummer. But my bandmates insisted that I be part of the recording and tour or they wouldn’t do it. It was incredibly gracious of them and I'm lucky to call them friends and brothers.

Thankfully, Karen pushed me to seek treatment and it saved my life. A new doctor prescribed medications that helped my depression and I was advised to stay active. I soon realized that I have the ability to take control of my situation, a lesson I have to remember every day.

After months of darkness, I finally saw a glimmer of light at the end of the tunnel and just that little bit of hope felt fantastic. I started feeling a little better each day and eventually found my way back.

I thank God for Karen; she was the light that I so badly needed. She, along with Patrick, Billy, Paul and Eric helped me realize how I lucky I am, and more importantly, that there's life after a Parkinson's diagnosis.

I also learned that depression is a very real and serious thing and it's ok to look for help and support. You owe it to yourself and the people that love you.

As for the band, I had to alter my approach to playing, but we were able to finish the album. We just completed a world tour and I was on stage for every show. Now we're getting ready for some U.S. dates and I can't wait. I feel like I've been given a second chance and I'm making the most of it.

See you on the road.

Parkinson's sufferer left humiliated after restaurant staff accuse her of being drunk and order her to leave

• 08:37, 8 March 2015
• By Craig McDonald

MARY Richardson, 57, who has uncontrollable movements due to the brain condition, said waiters at the Chef's World Buffet in Dundonald challenged her over what she was drinking.

Mary was forced to leave the restaurant

A PARKINSON'S sufferer says she was left humiliated by restaurant staff after they accused her of being drunk and asked her to leave.

Mary Richardson has suffered from the brain condition, which causes her to have involuntary movements, for 10 years.

She said waiters spent much of the evening staring at her before challenging her over what she was drinking.

Mary, 57, of Irvine, a gran-of-four, who also has a great granddaughter, described the incident, at the Chef’s World Buffet in Dundonald, Ayrshire, as “very unpleasant”.

She said: “I felt I should speak out to highlight the sort of thing people with a disability go through. I felt humiliated.

“I was at the restaurant with my son and his partner. We found the staff off-putting as soon as we got there.

“They kept staring at me, which I found quite embarrassing as I suffer from uncontrollable movement due to Parkinson's.

“A manager came up to our table and proceeded to lift my drink off the table and began to sniff it, asking me what was in it.

“I had a glass of white wine but, to dilute it, had poured some of the coke my son was drinking into my glass.

“My son explained I had Parkinson’s but the man accused me of being drunk and said I would have to go as he could lose his licence.

“My son was quite upset and repeatedly told him I was not well. The manager said I looked drunk and he couldn’t risk losing his licence.

“This happened in front of the whole restaurant which was packed and we felt totally humiliated. We just got up and left. I found the
situation quite unacceptable.”

http://health.einnews.com/article/253666498/-hx6-IxVCmHAsOlW