Little Miss Hannah » Parkinson’s Link

The Scientist Magazine: A Rare Chance

Mommy — Wed, 03 Feb 2010 04:03:14 +0000

http://www.the-scientist.com/article/display/57100/

Print Issue: Volume 24 | Issue 2 | Page 18

By Alison McCook

A rare chance

Over the course of 5 days last summer, an army of researchers and clinicians examined, poked, and prodded 1-year-old Hannah Ostrea at the National Institutes of Health (NIH). Experts in neurology, rehabilitation medicine, physical therapy, speech pathology, and anesthesiology gave the little girl an EEG, a test of her heart’s electrical activity (EKG), an MRI, a CT scan, X-rays, and a throat exam (laryngoscopy). All this testing was meant not only to help Hannah but in the hope that her rare disease could reveal something about another condition that affects 1 million Americans: Parkinson’s.

Hannah has Gaucher’s disease, and within hours of her birth, it was obvious something was wrong. Looking past her thick head of dark hair, and the fact that she could down an entire bottle of formula in 5 minutes, clinicians quickly saw that her spleen was massive, and her platelet counts were rock bottom. Her liver was expanding—in a few months it looked like she had a volleyball in her stomach. These are the classic signs of Gaucher’s, a rare, recessive genetic disorder in which the body does not produce enough of a lysosomal enzyme that breaks down the fatty substance glucocerebroside, causing it to glob up in cells of the liver, spleen, and other organs—including, sometimes, the brain.

But researchers have never seen the combination of mutations Hannah carries, so doctors couldn’t determine if she had the Type 2 or Type 3 form. Children with Type 2 typically die before their third birthdays, while those with Type 3 can live much longer. “They [wouldn’t] give us a prognosis,” Hannah’s mom, Carrie Ostrea, says. “They came out and said that to us. Which is fine by me.”Hannah has many classic Gaucher’s symptoms, such as developmental delays, and the inability to easily shift her eyes from side to side or up and down. But she also has some puzzling symptoms. For one, she only blinks once every 30 minutes or so—“you’ll have a staring contest with her,” Ostrea laughs. This is not a symptom of Gaucher’s disease, but it is a symptom of Parkinson’s.

Indeed, in recent years, researchers have been noting more and more crossover between the two diseases, and the hope is that insights into one will reveal secrets of the other.

In an October issue of the New England Journal of Medicine, Ellen Sidransky at the NIH and her colleagues found that Parkinson’s patients were five times more likely to carry a mutation in the gene associated with Gaucher’s disease. Furthermore, Parkinson’s patients with the mutation in the Gaucher’s gene tended to develop Parkinson’s earlier, and were more likely to have family members with Parkinson’s (N Engl J Med, 361:1651–61, 2009). It’s unknown how many people have signs of both diseases, Sidransky notes, but it’s “clearly dozens and dozens.”

Still, Parkinson’s and Gaucher’s are more different than they are alike. One comes from a deficiency of the lysosomal enzyme that breaks down glucocerebroside, the other likely from a deficiency of dopamine, and it’s largely unclear why the two diseases are linked, says Sidransky. Perhaps the lysosome plays a role in Parkinson’s; the protein misfolding that underlies Parkinson’s may be aggravated by mutations in the Gaucher’s gene.

Gaucher’s itself is an interesting model for trying to understand single-gene diseases, Sidransky adds. She and her colleagues like to invite patients with rare presentations of a disease to the NIH to study them and hopefully learn something about an entirely different condition. “I’ve always been convinced that focusing on one thing and becoming an expert helps you see connections” between that one question you’re investigating and other unanswered—perhaps even more significant—questions.

The NIH visits can be long, but Hannah held up fairly well, her mother says. She didn’t like waking up from the EEG and being tied down, and didn’t like the heart ultrasound, but the neuro-ophthalmologist got her to laugh hysterically by turning his video camera around so she could look at herself. “She just thought that was the funniest thing in the world,” Ostrea says.

The Parkinson’s Disease – Gaucher Disease link

Mommy — Fri, 23 Oct 2009 04:05:13 +0000

What we have known for a few months has finally started hitting the mainstream media now as well as some other medical sites. There are just a few….

Question is, now how can we capitalize on this and get the Parkinson’s community to start paying attention to our Gaucher kids?

Gaucher disease linked to Parkinson’s – Los Angeles Times
Mutant Gene Raises Risk of Parkinson’s (WebMD)
Glucocerebrosidase Mutations in Parkinson’s Disease New England Journal of Medicine (subscription)
Study Conclusively Ties Rare Disease Gene To Parkinson’s – Medical News Today

Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism

Mommy — Mon, 10 Aug 2009 12:07:45 +0000

http://www.ncbi.nlm.nih.gov/pubmed/19576930?dopt=Abstract

The Parkinson’s Institute, 675 Almanor Ave., Sunnyvale, CA 94085, USA.

A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson’s disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.

PMID: 19576930 [PubMed - as supplied by publisher]

Mutations for Gaucher disease linked to high risk of Parkinson’s disease

Mommy — Sat, 20 Jun 2009 17:55:30 +0000

http://www.phgfoundation.org/news/4676/

What’s the connection between Gaucher disease, a rare single gene disorder of metabolism that appears during childhood, and Parkinson’s disease, a common multifactorial disorder of the nervous system that occurs late in life? The answer lies in just a single gene (glucocerebrosidase or GBA), which encodes an enzyme required for lipid metabolism and storage within the lysosome. Numerous pathogenic mutations in this gene have been characterised, which result in Gaucher disease if present in both copies of the gene; these recessive mutations are generally assumed to be relatively harmless to the carrier.

However, numerous studies have linked pathogenic mutations within GBA with increased susceptibility to Parkinson’s disease. In perhaps the most definitive work to date [Mitsui J et al. (2009) Arch Neurol 66(5):571-6], researchers resequenced the GBA gene in over 500 cases of Parkinson’s disease and matched controls; whilst only 2 of the control subjects had any of the pathogenic mutations associated with Gaucher disease, 50 of the cases were heterozygous for one of 11 mutations in the gene. Having one of these mutations therefore confers a substantial and significant increased risk of developing Parkinson’s disease of nearly 30-fold (OR = 28.0, 95% confidence intervals 7.3-238.3), though individual mutations may be associated with various lower risks [Gan-Or Z et al. (2008) Neurology 70(24):2277-83]. In addition, patients with mutations in GBA were significantly younger at the age of onset of Parkinson’s disease than those without. In contrast, there was no statistically significant association between non-pathogenic mutations in GBA and Parkinson’s disease.

Comment: This research is important for three different reasons. First, by combining numerous pathogenic mutations in the GBA gene in a relatively large study, the work unifies various earlier and smaller studies linking the gene with Parkinson’s disease.

Second, it highlights a general paradigm shift from the common disease-common variant hypothesis within human genetics, which underlies the recent plethora of genome-wide association (GWA) studies, to the common disease-rare variant hypothesis. If the majority of genetic risk for common diseases is actually located in rare variants, not common polymorphisms, conducting resequencing analysis of specific susceptibility genes is the logical next step in the hunt for the genetic basis for all common diseases. Adopting such a strategy could therefore be substantially more fruitful than conducting ever larger GWA studies.

Third, and perhaps most significantly, the work raises serious ethical concerns over carrier screening for Gaucher disease, particularly within the Ashkenazi Jewish population (see previous news). According to the National Gaucher Foundation, the carrier status may be as high as 1 in 15 amongst Jewish people of Eastern European ancestry (and 1 in 100 amongst the general population). The current policy of the UK National Screening Committee is that carrier testing for Gaucher disease should not be offered, as it is treatable and can be relatively mild. However, those who are considering getting tested privately prior to becoming pregnant may now want to think again; a relative risk of ~30 is one of the largest genetic risks known, and may even have predictive ability (though further research is needed here). As Parkinson’s disease has a UK population prevalence of around 1% in the over 65’s (based on data from the Parkinson’s Disease Society), such information could potentially have enormous personal and societal consequences. Additionally, authorities face an even greater challenge – should people who have already had carrier testing be informed of the associated risk of Parkinson’s disease, or not?

Such ethical conundrums are only likely to increase as more and more genetic susceptibilities are discovered that have relevance to multiple diseases. To date, this has been a relatively small problem, as most of the susceptibilities discovered through GWA studies have been associated with extremely low risks (OR<2) and have very limited predictive ability. However, if the common disease-rare variant hypothesis is correct, we can expect significantly more issues of this nature to surface over the coming years. Policymakers and clinicians will need to bear this in mind when forming national guidance regarding genetic testing and screening.

Meeting with a Parkinson’s Neurologist

Mommy — Sat, 23 May 2009 22:18:46 +0000

Dr. William Ondo, Associate Director of the Parkinson Disease Center at Baylor, Houston

About a month ago, I sent an email to the Baylor Department of Neurology’s Parkinson’s group asking if I could meet with one of their clinicians to have Hannah’s symptoms evaluated. I explained that Hannah has neuronopathic Gaucher’s disease, and I wanted to talk with someone regarding the possible commonalities between the two diseases.

Yesterday afternoon, I got a phone call from the scheduler for this department saying that Dr. William Ondo, Associate Director of the Parkinson Disease Center and Movement Disorders Clinic is willing to consult with us and evaluate Hannah! Because she is a patient at Texas Children’s Hospital (Baylor’s pediatric hospital), all of her records and patient information was already accessible to him.

We meet with him in early July, right before we leave for NIH. The timing for this appointment is actually perfect, even though it is about 5 or 6 weeks away because it gives me more time to learn more about the disease processes of Gauchers and Parkinson’s.

Hannah’s lack of blinking reflex

Mommy — Fri, 22 May 2009 03:37:56 +0000

When we went to see Hannah’s ENT doctor a week or so ago, we were in the elevator on the way down, and one of the doctors going down said “Hey, your daughter doesn’t blink.” He didn’t say it in a concerned way, just more like he found it somewhat amusing that she kept her eyes wide open the entire way down.

So I had experimented with her for the rest of the afternoon. Sure enough, she can go for over 10+ minutes without blinking. I got tired of watching at that point! She isn’t having a seizure or anything, as she just goes about her day when this happens, playing with toys, drinking a bottle, taking a walk, etc. She has no problems interacting and has no changes in her personality when this happens. We also have no idea when this started because we had never noticed it before!

She will close her eyes if you touch her eyelash, and when she gets tired she will close her eyes (most of the way) to sleep.

So we shared this at our pediatrician visit, and he was just amazed at this symptom. So we now give her eye drops a couple of times a day to make sure her eyes are lubricated.

This is where it gets very interesting…

I asked Dr. Sidransky at the NIH about this new symptom, and her response was “That is very interesting and not typical of the eye movements in type 3 GD. It will be interesting to see what our neuro ophthalmologist thinks!”

I did some research into this, and you know what disease lack of blinking is a symptom of? PARKINSON’S DISEASE! Check it out, 1st on this list from MedicinePlus Encyclopedia/NIH. You can NOT tell me that these two diseases do not have a definite commonality of some sort in their disease process!

Hannah, who has a never-before-seen genetic mutation of neuronopathic Gaucher’s disease, has developed a symptom that is not a symptom of her Gaucher’s disease but IS a symptom of Parkinson’s disease, the very same disease that last week a 10-year-study and a second study solidifed the genetic link between the two diseases.

There is a VERY STRONG connection here!! Something that DESERVES to be looked at! Hannah and the other GD23 children truly MAY hold a key to understanding Parkinson’s disease, yet we can’t seem to get them to notice!

10-year-study solidifies strong link between Gaucher’s Disease and Parkinson’s Disease

Mommy — Wed, 13 May 2009 14:24:27 +0000

Today is an INCREDIBLE day in the world of Gaucher’s Disease! Two very important studies came out in the past day or two that have not only proven the strong link between Parkinson’s Disease and Gaucher’s Disease, but they will also open the eyes of many Parkinson researchers and biopharmaceuticals towards Gaucher’s Disease!

Is GD23 similar to a “childhood Parkinson’s Disease?” Now that this genetic link between PD and GD is here, it is time for researchers to realize that researching the babies of Gaucher’s disease with the neuronopathic type is critical to understanding Parkinson’s disease. Gaucher’s Diseases types 2 and 3 share so many of the same symptoms as Parkinson’s disease such as supranuclear gaze palsy, balance problems, fine and gross motor problems, fatigue, and swallowing problems. It cannot be just a coincidence that these two disease share so many of the same symptoms!

It is time to reach out to organizations such as the Michael J Fox foundation, the National Parkinson foundation, and the Parkinson Disease Foundation and say “Hey, our kids may hold the key to understanding your disease!”

Not only that, but the pharmaceutical companies that make Parkinson’s medications such as Sinemet, Stalevo, Parcopa, Cogentin, Artane, Eldepryl, Zelepar, and Azilect need to be looked at more closely to see if there is something within those medications that can be reformulated and used to possibly help our gaucher kids!

Association between Mutations in the Lysosomal Protein Glucocerebrosidase and Parkinsonism
A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson’s disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism. © 2009 Movement Disorder Society

Researchers believe they have found genetic cause for Parkinson’s disease
A team led by Shoji Tsuji of the University of Tokyo, and Tatsushi Toda of Kobe University discovered that those with a mutation in a gene called GBA are 28 times more likely to contract Parkinson’s disease. They now hope to use their finding to explain exactly how the disease is caused, and develop a treatment.

There are an estimated 150,000 cases of Parkinson’s disease in Japan. In 90 percent of the cases, however, they are the only members of the family to contract the condition, and the genetic component of the disease has never been identified. However, the team noticed that the GBA gene, which is responsible for causing an unusual condition called Gaucher’s disease, also showed a mutation in those with Parkinson’s disease. They examined 534 Parkinson’s patients and 544 healthy people, and found that 9.4 percent of those with the mutation suffered from the disease, and just 0.4 percent did not. They also discovered that those with the GBA mutation contracted the disease around six years earlier than those without.

“It’s the first time that a risk factor has been this clearly identified,” said Tsuji.

GBA gene (glucosidase, beta; acid)

Mommy — Fri, 08 May 2009 04:43:04 +0000

http://ghr.nlm.nih.gov/gene=gba

What is the official name of the GBA gene?

The official name of this gene is “glucosidase, beta; acid (includes glucosylceramidase).”

GBA is the gene’s official symbol. The GBA gene is also known by other names, listed below.

What is the normal function of the GBA gene?

The GBA gene provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Beta-glucocerebrosidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide).

How are changes in the GBA gene related to health conditions?

Gaucher disease – caused by mutations in the GBA gene: More than 200 mutations in the GBA gene have been identified in people with Gaucher disease. These mutations occur in both copies of the gene in each cell. Most of the GBA mutations responsible for Gaucher disease change a single protein building block (amino acid) in beta-glucocerebrosidase, altering the structure of the enzyme and preventing it from working normally. Other mutations delete or insert genetic material in the GBA gene or lead to the production of an abnormally short, nonfunctional version of the enzyme.

Mutations in the GBA gene greatly reduce or eliminate the activity of beta-glucocerebrosidase in cells. As a result, glucocerebroside is not broken down properly. This molecule and related substances can build up in white blood cells called macrophages in the spleen, liver, bone marrow, and other organs. Tissues and organs are damaged by the abnormal accumulation and storage of these substances, causing the characteristic features of Gaucher disease.

Parkinson disease – associated with the GBA gene

Growing evidence suggests an association between GBA mutations and Parkinson disease or Parkinson-like disorders that affect movement and balance (parkinsonism). People with Gaucher disease have mutations in both copies of the GBA gene in each cell, while those with a mutation in just one copy of the gene are called carriers. Some studies suggest that people with Gaucher disease and GBA mutation carriers have an increased risk of developing Parkinson disease or parkinsonism.

Symptoms of Parkinson disease and parkinsonism result from the loss of nerve cells that produce dopamine. Dopamine is a chemical messenger that transmits signals within the brain to produce smooth physical movements. It remains unclear how GBA mutations lead to these disorders. Researchers speculate that GBA mutations may contribute to the faulty breakdown of toxic substances in nerve cells by impairing the function of lysosomes, or mutations may enhance the formation of abnormal protein deposits. As a result, toxic substances or protein deposits could accumulate and kill dopamine-producing nerve cells, leading to abnormal movements and balance problems.

other disorders – associated with the GBA gene

Emerging research suggests an association between GBA mutations and a disorder called dementia with Lewy bodies. Lewy bodies are abnormal deposits of the protein alpha-synuclein that form in some dead or dying nerve cells. Specifically, they occur in nerve cells that produce a chemical messenger called dopamine. The features of this disorder are variable, but symptoms typically include a loss of intellectual functions (dementia), visual hallucinations, and fluctuations in attention. Affected individuals may also experience changes that are characteristic of Parkinson disease such as trembling or rigidity of limbs, slow movement, and impaired balance and coordination.

People with mutations in both copies of the GBA gene in each cell develop Gaucher disease, while those with a mutation in just one copy of the gene are called carriers. Research suggests that carriers have an increased risk of developing dementia with Lewy bodies, although it remains unclear how GBA mutations increase this risk. Researchers speculate that GBA mutations can alter the structure of beta-glucocerebrosidase and impair the function of lysosomes. As a result, alpha-synuclein may not be processed properly, allowing the formation of Lewy bodies.

Where is the GBA gene located?

Cytogenetic Location: 1q21

Molecular Location on chromosome 1: base pairs 153,470,866 to 153,481,111

The GBA gene is located on the long (q) arm of chromosome 1 at position 21.

More precisely, the GBA gene is located from base pair 153,470,866 to base pair 153,481,111 on chromosome 1.

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about GBA?

You and your healthcare professional may find the following resources about GBA helpful.

Educational resources – Information pages (2 links)
Gene Reviews – Clinical summary
Gene Tests – DNA tests ordered by healthcare professionals

You may also be interested in these resources, which are designed for genetics professionals and researchers.

PubMed – Recent literature
OMIM – Genetic disorder catalog (2 links)
Research Resources – Tools for researchers (3 links)

What other names do people use for the GBA gene or gene products?

Acid beta-glucosidase
Alglucerase
beta-D-glucosyl-N-acylsphingosine glucohydrolase
Beta-glucocerebrosidase
D-Glucosyl-N-acylsphingosine glucosylhydrolase
GBA1
GLCM_HUMAN
GLUC
Glucocerebrosidase
Glucocerebroside beta-Glucosidase
glucosphingosine glucosylhydrolase
Glucosylceramidase
Glucosylceramide beta-Glucosidase
Imiglucerase

See How are genetic conditions and genes named? in the Handbook.

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding GBA?

acids ; amino acid ; bacteria ; bone marrow ; carrier ; cell ; ceramides ; dementia ; digestive ; dopamine ; enzyme ; gene ; glucose ; hallucinations ; Lewy bodies ; lysosome ; macrophage ; molecule ; mutation ; nerve cell ; parkinsonism ; protein ; symptom ; tissue ; toxic ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References (14 links)

Calcium signaling in neurodegeneration

Mommy — Thu, 07 May 2009 18:04:48 +0000

http://www.molecularneurodegeneration.com/content/4/1/20

Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed.

In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival.

Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer’s disease, provides strong support for a role of calcium in neurodegeneration.

These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Novel Theory Explains Parkinson’s

Mommy — Fri, 01 May 2009 04:18:15 +0000

http://psychcentral.com/news/2009/04/30/novel-theory-explains-parkinsons/5622.html

By Rick Nauert, Ph.D. Senior News Editor
Reviewed by John M. Grohol, Psy.D. on April 30, 2009

In a study that reveals the clearest picture to date of neuron death in Parkinson’s disease, researchers at Columbia University Medical Center have found that a trio of culprits acting in concert is responsible for killing the brain cells.

The study, published in the journal Neuron, showed that three molecules – the neurotransmitter dopamine, a calcium channel, and a protein called alpha-synuclein – act together to kill the neurons.

The discovery gives researchers a new understanding of how to save the neurons, say the study’s authors, Eugene Mosharov, Ph.D., associate research scientist, and David Sulzer, Ph.D., professor of neurology & psychiatry at Columbia University Medical Center.

“Though the interactions among the three molecules are complex, the flip side is that we now see that there are many options available to rescue the cells,” says Dr. Mosharov.

The symptoms of Parkinson’s – including uncontrollable tremors and difficulty in moving arms and legs – are blamed on the loss of neurons from the substantia nigra region of the brain.

Researchers had previously suspected dopamine, alpha-synuclein and calcium channels were involved in killing the neurons, but could not pin the deaths on any single molecule.

The new paper, along with previous studies with Dr. Ana Maria Cuervo at Albert Einstein College of Medicine, shows that it is the combination of all three factors that kills the neurons.

The studies found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell’s ability to dispose of toxic waste that builds up in the cell over time. The waste eventually kills the cell.

The neurons will survive if just one of the three factors is missing, Drs. Sulzer and Mosharov also found. “It may be possible to save neurons and stop Parkinson’s disease by interfering with just one of the three factors,” Dr. Mosharov says.

That means that one drug already in clinical trials – which blocks the culprit calcium channel – may work to slow or stop the progression of the disease, an achievement none of the current treatments for Parkinson’s disease can accomplish.

Good Dopamine; Bad Dopamine

The idea that dopamine contributes to the death of neurons may seem paradoxical, since most Parkinson’s patients take L-DOPA to increase the amount of dopamine inside the cells.

The new study shows that it’s the location of the dopamine inside the neurons that determines its toxicity.

Most of dopamine inside the neurons is packaged into compartments that are shipped to the edge of the cell where the dopamine is released. The motor symptoms of Parkinson’s arise when the amount of dopamine released by the cells declines. L-DOPA improves symptoms by boosting the amount of dopamine released by the cells. As long as dopamine is confined inside the compartments before it is released, it is safe.

Outside the compartments in the cell’s cytoplasm, however, Drs. Sulzer and Mosharov found that dopamine – in concert with calcium and alpha-synuclein – is toxic.

New Idea for Treatment

A better treatment, the researchers say, may be to push more dopamine into the compartments where it has no toxic effect on the cell.

“That would be a magic treatment,” Dr. Mosharov says. “Not only would it stop cells from dying and the disease from progressing, it would improve the patient’s symptoms at the same time by giving their neurons more dopamine to release.”

Drs. Sulzer and Mosharov are currently working on genetic therapies that could accomplish this feat, but caution that it will be years before any such treatment is ready for clinical trials, if ever.

Source: Columbia University