PLEASE PAY ATTENTION TO YOUR PARKINSON'S POSTURE

Quality of Life Interventions for People Affected by Parkinson's Disease

March 11, 2016

One of the most recognizable physical manifestations of PD is something I call the "Parkinson's Stance". It is that classic C-shaped stoop, combined with claw-like hands out in front. The "conventional" wisdom indicates that this is the ultimate fate of People with Parkinson's. It does seem to be widely accepted, with a shrug of the shoulders - by those who can shrug them - that this is our ultimate destiny. Yet the absolutely terrible posture of the Parkinson's Stance is a serious health risk in its own right and I believe we need to seriously begin challenging the "wisdom" that this is how we have to end up. Or at least demonstrate that it is well worth doing whatever we can every day to delay the onset for as long as possible.

     

  

We all know that bad posture = bad health and that this is a very vicious cycle under any circumstances. For PwP, the Stance is a very vicious thing indeed. It amplifies the symptoms of PD greatly and represents a self-accelerating decline. Just think about it. We all know how bad spending hours hunched over a computer keyboard is for us. The long term consequences of ignoring typing posture are serious. Carpal tunnel and thoracic outlet syndrome being just two examples. So imagine how bad for health standing or sitting in the Parkinson's Stance is for any length time. Now consider what this does to the wellness of a human body when the Stance becomes a semi-permanent state.

I have been very fortunate to catch this early, thanks to my co-founder Deb, who has a keen interest in posture correction. Deb showed me some very simple techniques which i could implement even when quite immobile. Deb taught me one such technique in particular which I have been practicing daily as shown in the video clip from 3rd February 2016.

Thanks to this intervention, I have stopped stooping into the Parkinson's Stance, unless very stressed. And the change was quite quick. After a few weeks of practicing posture correction techniques, I was delighted when Deb compared a snapshot of me with an online photo of perfect posture of someone without chronic illness simply standing and she gave me a grin and a big thumbs up.

I urge all People with Parkinson's to consider that this is a priority health area to address. It is possible to take corrective and preventative steps against the Stance. My own experience does show that it is possible have dramatic effects with daily persistence.

So let's do everything we can to make the Stance a much less recognizable aspect of PD.

For our own sakes.

TRANSCRIPT

Hi, it’s Dr Gary Sharpe, it’s Feb 3rd 2016.

I’m in a state of bradykinesia again, and today I want to talk to you about posture.

So one of the main symptoms of PD is that long term your body gets pulled into a C-shape. You crouch over, and you can’t really see this but my hands are… if I can get them up… my hands are claw like and in front of me.  And it’s very hard to get my shoulders back.

Not good for you and not good for your balance

The main symptom, the body gets pulled into this C-shape. And for me the pain, the pain and stiffness, is right across the shoulders at the back, and it can be very painful.

One thing we have been thinking about in our Out-Thinking Parkinson’s Series is how can we correct this, I can’t correct it myself because my brain isn’t allowing me to move my muscles in such a way that I can get my shoulders back.

I found this, a metal tube, just a hollow metal [aluminium] tube. If I can just get this into the crook of my shoulders {elbows}, then it corrects the posture quite well. So it’s just sitting there, it’s not painful. Now my shoulders are back, and I can actually relax my arms. This stops me going into a C-shape, so it’s countering what the Parkinson’s wants to do.

I’m finding the more I do this, the easier I can correct myself without the aid of the external bar, but I tend to do this quite a lot when I’m in a state of bradykinesia, because it relaxes some of the muscles, it prevents some of the pain. And I can sit down like this for quite a while. And again my shoulders are back. I can even correct these claw like hands by putting my fingers together and that’s quite a relief as well.

So I can walk around like this, and at the moment I’m shuffling, because I’m not being mindful, I’m shuffling around, but I find that this also, if I’m actually mindful of the walking, I can walk normally, easier. You can’t really see this but I’m going to take big steps. Parkinson’s people should not be able to do that very easily. I can do it. It’s because I think, because my posture is good, my whole kinetic chain is improved, so instead of my body feeling like it’s going to fall over, it feels safer, so it let’s me take big steps. There you go.

So there seems to be a cumulative effects of doing this, of just holding myself in this position. Essentially I can get my hands down behind me, on the back of my thighs, which is pretty hard to do normally in Parkinson’s. Can’t really see but… I’ll walk again.  So I just walk around like this and just walk around and it is quite a relief on some of the pain of that goes with Parkinson’s.

I hope it is going to have a long term effect on correcting my posture

So stay tuned.

Look, I can even push the button there.

http://www.outthinkingparkinsons.com/video-blog/posture

Posture and Safety

Older but good videos:

Parkinson's and others with movement issues seldom make the connection, but falling, pain, choking, shouting for help and getting out of a chair can all be improved with good posture!

Posture Lesson for Parkinson's Disease

Parkinson's and others with movement issues seldom make the connection, but falling, pain, choking, shouting for help and getting out of a chair can all be improved with good posture!Sherryl Klingelhofer

Patrick's posture lesson that explains 8, easy to follow anatomical landmarks and corrective strategies to improve postural integrity for people living with Parkinson's Disease. Patrick is committed to developing evidence based exercises for PWP that improve quality of life. Patrick LoSasso

International Stem Cell Corporation's (ISCO) Mission to Treat Parkinson's Disease Coming into Focus

March 11, 2016

March 11, 2016 (Investorideas.com newswire)

 International Stem Cell Corporation (OTCQB: ISCO) builds shareholder value through its research with stem cells, otherwise known as cells that can both proliferate (divide) and change (differentiate) into more specialized cells, such as skin, nerve or liver cells. The most powerful stem cells are known as ‘pluripotent', as they have the promise of becoming virtually any cell in the human body. The first pluripotent stem cells to be studied were embryonic stem cells (ESC) taken from donated human embryos. ISCO's new class of pluripotent human stem cells are derived from unfertilized eggs. These stem cells, known as human parthenogenetic stem cells (hPSC) avoid the ethical issues associated with ESC while retaining many of the advantages.

The company's work does not begin and end with research. International Stem Cell Corporation's primary goal is to transform its research into treatment for those suffering with moderate to severe Parkinson's disease, and if recent developments are any indication of the company's progress in this area, the recent announcement that enrollment has started for its upcoming phase I clinical trial should remove all doubt. The trial is scheduled to take place at the Royal Melbourne Hospital in Australia.

In a news release, Dr. Russell Kern, executive vice president and chief scientific officer of ISCO, recently noted, "Enrollment in this trial is an important milestone… Promising preclinical results support our expectation that ISC-hpNSC will bring a long-needed solution for patients suffering from Parkinson's disease."

ISCO is a publicly traded biotechnology company which developed a powerful new stem cell technology called parthenogenesis that could significantly advance the field of regenerative medicine by addressing the problem of immune-rejection. Parthenogenesis (from the Greek parthenos, meaning "virgin" and genesis, meaning "birth") uses unfertilized human eggs to create hpSC that can be immune-matched to millions of people. A relatively small number of hpSC lines could provide sufficient immune-matched cells to cover a large percentage of the world's population.

The company's human cell culture products also comprise adult stem cells and reagents for regenerative medicine; human prostate cells and specialized media to study prostate disease; human renal and bladder cells and media to study renal and bladder diseases; human corneal cells and media for the study of corneal disease; and other cell culture reagents and supplements for the growth, staining, and freezing of human cells. International Stem Cell Corporation was founded in 2001 and is headquartered in Carlsbad, California.

For more information, visit www.internationalstemcell.com

http://www.investorideas.com/news/2016/biotech/03111.asp

Michael J. Fox attends State Dinner amid reports he's 'losing battle' with Parkinson's

MICHAEL J. FOX put on a brave face to attend a State Dinner held at the White House last night amid reports he's "losing his battle" with Parkinson's Disease.

Michael J Fox attends state dinner with wife Tracy Pollan

By LAURA WITHERS

 Fri, Mar 11, 2016 

The star attended the bash in honour of Prime Minister Trudeau and Mrs. Sophie Trudeau of Canada, alongside his wife Tracy Pollan.

Despite reports claiming the illness is now "taking its toll" on the actor's body, Michael is still insistent on attending work events.

Although he was looking a little more frail and tired than usual, he was more than happy to stop and smile for the waiting photographers.

Michael and his wife appeared to be in good spirits 

Dressed to impress for the occasion, the Back To The Future star wore a classic, black tuxedo and bow tie, which he teamed with a crisp white shirt.

Michael and his wife attended the event held at the White House

Meanwhile, his wife Tracy looked stunning in an elegant navy floor-length gown. 

Despite continuing to attend work events, sources have now said that the disease has been getting a lot worse recently as the star was seen struggling to get into a car outside Hollywood restaurant Craig's.

“It was heartbreaking,” an insider told RadarOnline.com. “Michael’s bravery knows no bounds. But as the disease takes its toll on his body, even he is beginning to see that his battle is a losing one.

Michael was pictured at the DCA Washington Reagan National Airport yesterday afternoon

“Michael sees every day as a gift, as well as an opportunity to help other sufferers,” they continued.

During a chat with David Letterman, Michael described the day he received his diagnosis.

He said: "It was pretty scary. I was 29 years old and so it was the last thing I expected to hear.The 54-year-old learned he had the illness back in 1991, before publicly announcing it after undergoing brain surgery to control his shaking in 1999.

http://www.express.co.uk/celebrity-news/651751/Michael-J-Fox-attends-State-Dinner-amid-reports-hes-losing-battle-with-Parkinsons

Why I Refuse to Give in to Parkinson's Disease

March 11, 2016
Steve AltenAuthor and scribe
                                        

Steve Alten

The appointment with the neurologist was on March 21, 2007. I was 47 at the time and in pretty good shape. I had never smoked, drank, or took drugs. I worked out four to five times a week. But something was not right. It all began as horrible toe and foot cramps. The little finger on my right (dominant) hand would twitch, and when I played the drums I noticed my right leg was wearing down as if lactic acid was running through my quadriceps. My gait changed; my right arm no longer swinging naturally. Stress brought out the worst of these symptoms; I remember being in a heated phone call where my right leg started bouncing uncontrollably. Finally, I decided it was time to see a specialist.On my visit with the neurologist, he took notes, had me perform half a dozen movements and pronounced me with early onset Parkinson's. He explained PD was caused by a lack of dopamine in the brain. When dopamine is low, movement becomes impaired. This leads to trembling of the limbs, rigidity, slowness, impaired balance, and a Frankenstein-like walk. PD Meds: Not All That Glitters is GoldThe more I researched Parkinson's, the more concerns I had about the drugs, which must be steadily increased as the brain gets used to them. Inevitably, this leads to scary side-effects like dyskinesia, the wild involuntary movements that Michael J. Fox sadly experiences. My doctor tried assuring me I would be okay -- "if and when the dyskinesia gets bad, we'll schedule you for brain surgery."Say what? Essentially, part of my skull would be removed to allow electrodes to be attached to my brain. These wires would run down the inside of my neck to a control switch installed in my chest (to regulate the voltage) which would halt the tremors... temporarily.I agreed to Azilect, a non-dopamine med with no side effects that could potentially delay my symptoms, but that was it. For now, I'd fight the stiffness with exercise and stretching.I fought the good fight for seven years until the summer of 2014 when my symptoms took a sharp turn for the worse. The scariest was bradykinesias -- a momentary freezing where I'd find myself stuck in neutral. I was also bent over and had to use the walls as brakes. Balance became a major issue and I got into the habit of taking three involuntary baby steps backward. 
I put aside my writing; every waking moment now devoted to researching and finding alternative treatments. I tried using a hyperbaric chamber but after 28 sessions felt no improvements. I flirted with taking mucuna pruriens but feared the side effects of a substance that no one seemed to have a handle on. A Parkinson's patient introduced me to a biochemist in Europe who had developed an all-natural vegetable extract possessing similar benefits of Sinemet without any side-effects. He sent me sample jars, but it didn't seem to help.I was depressed and began to hate my daily existence, especially the strain it was placing on my family. I never contemplated suicide, but the thought of dying no longer scared me.The low-light came one night while taking the garbage out. I took three steps backwards -- and fell butt-first into one of the recycling bins! I was bruised and scraped up and I couldn't get out; I was like a turtle stuck on its back. Tears of anger poured down my face as I struggled to stand, but failed to gain enough leverage. Finally, I rolled over sideways and crawled out of the cursed trap. The next day I waved the white flag and called my neurologist. 

"Acceptance does not mean resignation. It means understanding that something is what it is and there's got to be a way through it. Our challenges don't define us. Actions do." --Michael J. Fox"

Get me the drugs!"He prescribed three Sinemet a day, plus a Neupro patch. The transition wasn't easy. I felt horrible. And then one night a bad reaction led to an amazing discovery. My wife had taken the kids to visit her cousin. Alone in the house, I awoke to a frightening feeling -- a cold, paralyzing numbness was creeping from my feet up into my legs; my body shutting down! I was terrified and realized if I didn't force myself out of bed I might not wake up. I stumbled to the kitchen in a state of panic and desperate -- took a spoonful of that vegetable extract. Within minutes, a warm sensation replaced the cold. I felt life returning to my body.It seems the extract may have latched onto the Sinemet and had a synergistic effect. After a month of trial and error, I figured out how to alternate the two, reducing my symptoms by 70-80 percent while only taking two Sinemet a day. 

Over the last three months, I've been using Howard Shifke's Parkinson's Recipe for Recovery, written by a fellow PD patient who cured himself using different movements and a vegan diet. It makes absolutely no sense but I always feel better after doing it. I'm also five weeks into a detox program that shows promise. No matter, what, I refuse to accept this disease as anything other than a speed bump. As Dylan Thomas wrote, "Do not go gently into that good night... rage, rage against the dying of the light.

"http://www.huffingtonpost.com/steve-alten/why-i-refuse-to-give-in-t_b_9440936.html

Helen Mirren: 'it's time we all understood Parkinson's disease'

March 11, 2016

Oscar-winning actor calls for a revolution in attitudes to sufferers of the degenerative neurological condition

 Helen Mirren in Moscow for a private screening of her film The Last Station. Photograph: Epsilon/Getty Images

Helen Mirren is calling for a revolution in attitudes towards Parkinson's disease so that sufferers are no longer mistaken for drunks nor end up in social isolation because they are seen as "weird".

The Oscar-winning actor wants education campaigns to tell people how to recognise the constant involuntary movements that characterise the degenerative neurological condition, which 120,000 Britons have.

Speaking exclusively to the Guardian during a trip to the UK, Mirren talked for the first time about how a close friend's 10-year struggle with Parkinson's had helped her realise the difficulties which sufferers face, including worsening physical disability, mental anguish and, for some, social stigma.

Mirren – who won the best actress Academy award in 2007 for her performance in The Queen – demanded an end to what the charity Parkinson's UK claims is the "disgrace" of a UK postcode lottery in NHS support services for sufferers, such as access to specialist nurses and physiotherapy.

"I have sympathy for their campaign for equitable access, absolutely," she said. "It's terrible that one person living 15 miles away from another does not have access to something while the other person does.

"A good friend of mine, a photographer who I've known for 30 years, was diagnosed with Parkinson's about 10 years ago. He's very wobbly on his feet, uses a stick, has shaking hands, has an increasing problem with walking, falls and can't rely on his balance. He's physically very fragile. It has limited his life and restricts his place in the public world.

"Parkinson's is a slow but inevitable process. It's hard living with it on a daily basis. The difficulty facing people with it is that they never quite know 'Can I or can't I do this today?' That's what makes normal, everyday life more and more difficult, because, for example, you can drive perfectly well for five minutes and then suddenly not be able to do something you thought you could do."

Lack of public awareness means some sufferers are wrongly assumed to be drunk because their hands may be shaking or limbs flailing.

"That must be the worst thing – just awful, terrible and so mortifying – to see people looking at you [and assuming you are drunk]," said Mirren.

"People with Parkinson's are not some weird people on the edge of human experience."

and for the public to have a real understanding of it, as they're beginning to have with autism.

"You know, 20 years ago autism was this weird, spooky, terrifying thing and now it's much, much better understood. It's the same with Parkinson's.

"The public here need to have a similarly open discussion about Parkinson's. People like my friend are as valuable and important as you and I and anybody else, and they must not feel that the world is such that they have to hide themselves away. That's horrible and ridiculous."

Those who passed a person with Parkinson's on the street needed to start seeing them as no more unusual than someone with a cast on a broken limb.

"But we're a long way off that at the moment because the physical manifestations of it are such that we don't understand them when we see them," Mirren added.

Steve Ford, chief executive at Parkinson's UK, said: "We are delighted that Helen Mirren is showing her support for our Fair Care for Parkinson's campaign and understands the need to change attitudes to Parkinson's – among the public, healthcare professionals and in government. So often people's symptoms are misunderstood and people are treated without respect."

Parkinson's UK is funding a new study, to be conducted by psychologist Dr Cathy Craig of Queen's University Belfast, into whether sufferers can improve their balance, co-ordination and mood by using Nintendo Wii games consoles.

"The Wii has the ability to help people improve their movement, not just fitness," said Craig. "People report improvement in their balance, which helps prevent falls that are common with Parkinson's.

"Others find that the social side of using the Wii really improves their mood and combats the anxiety and depression that many people with Parkinson's experience."

Mirren helps promote Nintendo's Wii Fit games.

http://health.einnews.com/article/316108792/ldnzeYIuuyPDfi1v

What I Learned Training for 'American Ninja Warrior'

03/11/2016

                                                         Allison Toepperwein 

About six months ago, I embarked on a journey. It began floating down the river, making friends with the current. "A bunch of buddies and I are going to 

do a mud run in November. You should do it with us!" Little did I know the impact those words would have.

As I trained for that mud run, angels began whispering in my ear that I should apply to be on American Ninja Warrior, a obstacle course TV game show.

I walked in Iron Sport gym in Houston, the night before the application was due. I felt pretty confident in my ability, until I saw my competition. I was met by mainly men in their early 20s. Normal-looking guys, until they started swinging from the rafters and scaling walls on their fingertips. I immediately felt overwhelmed and out of my league. But, I decided I was there, so I stretched.

On our first obstacle, I told the owner of Iron Sport, American Ninja Warrior Sam Sann, of my big obstacle: Parkinson's. He told me emphatically, "I can help you! I believe my exercises will help you!" I believed him.

The first obstacle was the rings. I couldn't swing from one to the next relying on my left arm to hold my body weight. Instead, I tried leading with my right arm. I was told that was harder, and they were right. But, with Parkinson's on my inferior arm, I didn't believe that was an obstacle I could overcome.

There were other apparatuses I was able to accomplish, like the ropes and peg board. After an hour and 20 minutes of balance and upper body focused challenges, it was time for conditioning. Twenty-five minutes of conditioning my body seized up and my forearms felt as if they would rip. I had tears in my eyes and I wished for them to fall, as to quench my extreme thirst. I apologized to Sam for my trembling. He said, "My workouts make anyone shake!"

After my I submitted my application, I waited another month, before going back for the torture. That is when the clouds parted and the angels sung. I completed what seemed impossible the first session, the nunchucks. Narrow aluminum pipes requiring grip strength to prevent sliding right off. I was on a dopamine high the remainder of the night.

I was getting the swing of things and began anticipating my next visit. This time, I brought a friend/witness/photographer. I tried the rings, telling my friend, I couldn't complete it yet, because of my PD. I told her I thought I had the strength, but I had to get over the hang-up with my left arm, mentally. Just in case, I had her video. 

I faced my fears of trusting my left arm. I stopped fighting to control it. I no longer resisted and instead I just let go. And when I let go, I flew!

On a dopamine high from flying, I saw rings of another color. As I stood looking up at them, I thought it defied physics and would be impossible, but again I tried.

I walked out of that session feeling like I was a badass! (Sorry for cursing.) I let go of my fears, and checked my "disability" at the door, and forgot to pick it up on the way out. That day I flew and felt as though I was soaring until the following day.

Each time I've go into Iron Sport, I accomplish a little more. Each time I'm left with an enormous dopamine high. Each time, I've itched at the chance to go back.Yes, I have Parkinson's disease and I tried out for American Ninja Warrior. Yes, would love to be on the show for a multitude of reasons. However, what I've learned training to be a ninja has far outweighed the benefits of being on TV. 

One of the big issues since my diagnosis, has been seeing my disease as a liability. The biggest outcome from training for American Ninja Warrior is that no longer the case. Maybe it's that I can do more pull-ups than most of the 20-something guys at the gym. Or maybe it's that I'm achieving success at the obstacles at Iron Sport. Or maybe it's that I'm stronger both physically and mentally, than anyone else around me. Parkinson's disease has allowed me, pushed me even, to achieve these feats. It's given me the drive to get up and try again, when tears are pooling and pain is constant. 

My disease is the catalyst I needed to be the very best mother and person I can be. So what if I have to take meds three times a day. Who cares that I shake a little when I wake up, get nervous or when my meds wear off. The greatest lesson I could have learned from American Ninja Warrior has been realizing PD is NOT a liability to me. And if you think it is, then YOU are the liability!

http://health.einnews.com/article/316048110/v7xZZ3ReK0RZ8qaz

Scientists Discover How to Make Better Animal Models of Parkinson’s Disease, Potentially Leading to Drug Treatments

By Magdalena Kegel

March 11, 2016

French scientists have discovered a mechanism preventing Lewy bodies from forming in laboratory animals, allowing for the development of better animal models of the disease. This will likely speed up research into the disease and aid in the development of drug therapies.

The main feature of the brains of Parkinson’s patients is the presence of protein clumps called Lewy bodies, which are made up mainly of the protein alpha-synuclein, normally involved in the transmission of neuronal signals. But in Parkinson’s disease, the protein aggregates and forms so-called fibrils inside neurons.

After nearly a century of research, scientists still don’t know why Lewy bodies form, nor exactly how they contribute to the disease. This is largely because researchers have not succeeded in reproducing Lewy bodies in animal models of the disease, hampering research and drug development.

In humans, scientists know that Lewy bodies form when alpha-synuclein is produced at twice the normal amount, but when attempting to overexpress the human protein in mice, no Lewy bodies are formed.

Mice express three different variants of their own synuclein. The research team at the École polytechnique fédérale de Lausanne (EPFL), led by Hilal Lashuel, figured that mice synuclein variants might somehow interfere with Lewy body formation. Therefore, they produced mice that lacked either one or all three of the mouse synuclein variants.

The study, published in the journal PNAS, showed that when cultured mouse neurons were deprived of either one or all three variants, clumps similar to Lewy bodies formed when human alpha-synuclein was high. The team observed similar results when they assessed mice brains.

The study, ”Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease,” also found that the mouse variants directly interact with early forms of the human alpha-synuclein during the aggregation process of human alpha-synuclein, preventing the formation and spread of Lewy bodies.

Using this knowledge, the team developed and characterized new models of Parkinson’s disease. Lashuel now hopes that these findings will advance the development of cell and animal models that mimic features of Parkinson’s disease and aid in the development of new drugs.

“We now have a very well-characterized model that offers a powerful tool for rapid screening of molecular pathways involved in Parkinson’s disease,” Lashuel said in a press release. “But because it can also allow us to understand how human alpha-synuclein forms fibrils inside neurons and how that contributes to the progression of the disease, we can develop better drugs and intervention strategies to prevent this disease.”

http://parkinsonsnewstoday.com/2016/03/11/scientists-discover-how-to-develop-better-models-of-parkinsons-disease/

A new link between pesticides and Parkinson’s disease

By lussy · March 11, 2016

Environmental factors are thought to be an important cause of Parkinson’s disease. A new study shows that rats chronically treated with the mitochondrial inhibitor rotenone, a common pesticide, develop neuropathological and behavioral symptoms of Parkinsonism.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, affecting almost 1% of the population over 65. Although the symptoms and neuropathology of PD have been well characterized, the underlying mechanisms and causes of the disease are still not clear. In this issue, Betarbet et a report that chronic administration of rotenone, a widely used pesticide, can induce the major features of PD in rats. This remarkable observation not only provides a new animal model for the study of PD, but will also reinvigorate interest in the possible role of exposure to pesticides and other toxins as a cause of human neurodegenerative disease.

PD is characterized clinically by rigidity, tremor and bradykinesia, which result from the progressive death of dopaminergic neurons in the substantia nigra. The defining feature of idiopathic PD is the accumulation of Lewy bodies in the substantia nigra and other brainstem nuclei. Classical Lewy bodies are small (5−25 m) spherical inclusions, consisting of a dense granular core surrounded by a halo of radiating filaments, and it is suspected that these deposits are involved in triggering the death of dopaminergic neurons.

The etiology of PD is diverse and complex. Some cases can be attributed to genetic factors, and several mutations have recently been described that lead to familial PD Two of these mutations, in the genes encoding parkin and ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), lead to diseases that are somewhat distinct, both clinically and pathologically, from idiopathic cases, and how they relate to classical PD remains unclear. The third class of mutations, in contrast, has been more informative. These affect the gene for synuclein, a synaptic protein of unknown function that subsequently proved to be a major component of the filaments associated with Lewy bodies. In addition, -synuclein is the major constituent of several other disease-specific lesions, including cortical Lewy bodies, swollen neurites (known as Lewy neurites) and glial cell inclusions. The term ‘synucleinopathy’ has been coined to designate this broad class of neurodegenerative disorders, and the genetic link between -synuclein and familial PD suggests that Lewy body formation may be an important trigger in the disease process. Further evidence for this idea comes from experiments in which synuclein is overexpressed in flies or mice. Mutant flies carrying the human gene undergo adult-onset loss of dopaminergic neurons, accompanied by formation of filamentous synuclein inclusions as well as locomotor dysfunction. In mice, overexpression of human synuclein results in impaired motor function, neuronal degeneration and perikaryal, neuritic and (unexpectedly) nuclear synuclein aggregates. These deposits, however, are not filamentous, suggesting that the mechanisms leading to polymerization of synuclein fibrils are more complex than mere protein accumulation.

Genetic mutations can provide important clues to disease mechanism, but most PD cases are sporadic rather than familial, and environmental factors have long been suspected to contribute to the disease. One possibility is that an infectious agent may be responsible—Parkinsonism can follow von Economo’s encephalitis, a disease that reached pandemic levels in the early twentieth century—but no infectious agent has ever been identified An alternative possibility is that a toxin may be involved. Interest in this idea was driven by the appearance, in the early 1980s, of PD-like symptoms, including damage to the nigrostriatal dopaminergic system, in heroine addicts who had been exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a substance inadvertently produced during the attempt to synthesize a meperidine analog as a ‘designer drug’. MPTP induces acute and irreversible PD-like symptoms in monkeys as well as humans, but although its effects resemble those of idiopathic PD in many respects, providing a useful animal model, it does not induce Lewy body formation, either in humans or in animals

MPTP is toxic because it is converted into 1-methyl-4-phenylpyridinium ion (MPP+), which is selectively imported into dopaminergic neurons by the plasma membrane dopamine transporter. MPP+ accumulates in mitochondria, where it inhibits complex I (also known as the NADH dehydrogenase complex), one of the enzymes involved in oxidative phosphorylation. This raises the possibility that other inhibitors of complex I might also induce PD-like symptoms. Betarbet et al. have now tested this hypothesis using rotenone, a plant-derived inhibitor of complex I that is widely used both as a household insecticide and as a tool for eradicating fish (as part of fishery management programs).

The authors show that chronic i.v. administration of rotenone in rats produces effects that closely resemble human PD. The treated rats showed several cardinal behavioral features of the disease, including bradykinesia, postural instability, unsteady gait and some evidence of tremor. Histological examination indicated that rotenone treatment leads to progressive degeneration of the nigrostriatal dopaminergic system. Importantly, the surviving nigral neurons developed intracytoplasmic synuclein-rich inclusions that appeared similar to Lewy bodies by light and electron microscopy. Although some of these inclusions resembled ‘pale bodies’, presumptive precursors of Lewy bodies, others showed the characteristic features of authentic human Lewy bodies, including a distinct core surrounded by a fibrillar halo.

Unlike MPP+, which targets dopaminergic neurons because of its affinity for the dopamine transporter, rotenone can cross cell membranes and is therefore likely to affect all cells. Consistent with this, the authors confirmed that their treatment protocol led to complex I inhibition throughout the brain. However, they observed PD-like symptoms even at low concentrations, for which the degree of complex I inhibition is insufficient to significantly impair oxidative phosphorylation in the brain. This argues against ATP depletion as a mechanism for the loss of dopaminergic neurons. An alternative possibility, consistent with earlier suggestions, is that free radicals, such as superoxide anions, which are known to result from mitochondrial inhibition, may be responsible for the damage. Oxidative damage has long been implicated in neurodegenerative diseases, and it may be of particular importance in synucleinopathies, given the extensive and widespread oxidative modification of -synuclein in the deposits characteristic of these diseases Moreover, oxidative damage is at least partly responsible for the toxic effects of MPTP.

The question remains as to why rotenone, which inhibits complex I throughout the brain, should preferentially target dopaminergic neurons. The likely answer is that these neurons are particularly sensitive to oxidative stress because of the permanently elevated level of free radicals generated by dopamine metabolism and auto-oxidation. This may not be the whole story, however, because the authors observed differences in rotenone vulnerability between different populations of dopaminergic neurons within the substantia nigra, and between dopaminergic fiber projections and cell bodies. Clearly, there may be other factors at work, which remain to be clarified by further study.

Figure 1 summarizes some of the complex mechanisms that may be involved in PD and related diseases. The importance of -synuclein Lewy body pathology is not fully understood, but it is likely that the accumulation of -synuclein filaments, possibly as a consequence of oxidative damage, contributes to impairment of cellular function, eventually resulting in cell death. Unraveling the interplay of genetic and environmental factors will be crucial in dictating the future direction of research and in guiding the development of novel therapies for synucleinopathies. The results of Betarbet et al. should provide a valuable new model for assaying the efficacy of such treatments.

The new study also has important epidemiological implications. Rotenone is a naturally occurring substance that is eventually degraded in the environment, and as such it is considered to be benign compared to many other pesticides. The results of Betarbet et al. are likely to raise new questions about its safety, although whether rotenone exposure contributes to the incidence of PD remains to be determined. Nevertheless, the effects of chronic rotenone administration observed here may be representative of the possible effects of exposure to low amounts of other environmental toxins, yet to be identified. Although genetic factors certainly contribute to vulnerability, the most important risk factor for PD is age, consistent with the idea that chronic exposure to low levels of noxious substances over time may drive a molecular chain of events that eventually leads to PD. Chronic effects may also be compounded by episodes of acute neuronal death, perhaps as a result of transient toxin exposure. The new study will revitalize the search for environmental toxins, including other pesticides, that may contribute to the etiology of this disease.

http://diseasestreatment.info/a-new-link-between-pesticides-and-parkinsons-disease/