Please read my Jan 10, 2015 entry, “We get yet another clue from alpha-synuclein” in my Psychology Today blog, Neurogenetic Journey; A View From Both Sides of the White Coat: http://bit.ly/1w7QpUt
Please read my comments on Peg O’Connor’s blog about Robin Williams, Parkinson disease, and the “hijacking of the brain” by drugs on Psychology Today: http://bit.ly/1xxyjQf
Once again “our” alpha-synuclein (SNCA)—the protein that my team linked to Parkinson’s back in the ’90’s—is in the forefront of potential treatment approaches! A team at UCLA has reported improvement of PD-like symptoms in a mouse model (mice that over-produce SNCA and demonstrate Parkinson disease-like symptoms) with a drug being studied to treat a rare genetic disorder, Gaucher disease.
Gaucher disease occurs when two carrier-parents pass on a gene which prevents the body from producing an essential enzyme, glucocerebrosidase (GCase). In 2011, a team at Massachusetts General Hospital described the interaction of Gauchers and Parkinson’s in the same pathway: disruption of the GCase pathway results in SNCA deposits and as SNCA levels rise, the Gaucher’s associated pathway is inhibited. This suggested that medications used for one might benefit the other.
The drug, AT2101, is a “chaperone” drug which helps guide malfunctioning enzymes to where they need to function. In the mice that over-express SNCA, (as in PD patients) the drug improved motor function, stopped brain inflammation, and reduced SNCA, suggesting its potential effectiveness for treating Parkinson’s.
Keep the faith.
The following recently appeared on the American Parkinson Disease Association website.
On July 31st, the Austrian biotech company, AFFiRiS AG announced the results of an early-stage trial of a vaccine intended to treat Parkinson’s disease. This is the first such study in Parkinson’s, although there has been work with similar strategies in Alzheimer disease. The vaccine called PD01A targets the protein alpha-synuclein, which builds up in the brain in Parkinson’s. The main goal of the AFFiRiS study was to assess safety. The study was small, involving only 36 people, but the outcome was positive in that the treatment appears to be safe. The numbers were too small to conclude anything about whether or not it was effective, but this success does allow this new treatment approach to move on to larger studies.
Dr. Alice Lazzarini is a geneticist who participated in the discovery of the importance of alpha-synuclein, and also a PWP (Person with Parkinson’s disease). She offered her own perspective on this news:
“It began, for me, in 1990 when Dr. Roger Duvoisin recruited me to his department of Neurology at UMDNJ-RWJMS to work on the genetics of ataxia. However, no one worked for “Dr. Parkinson,” as he was known by the neurology community, or “The Boss,” as he was affectionately known by his faculty, without getting hood winked into working on Parkinson’s.
One day, The Boss came to me and said, “Alice I want you to prove Parkinson’s is genetic.” I gulped, rolled my eyes, and wondered how I was ever going fulfill his tall order. Roger had been a strong proponent of an environmental cause of PD, but reassessing data from his twin studies and finding the Contursi Kindred—a family with autopsy proven Parkinson’s—made him publically reverse his own position.
Up until then, there had been little credence given to PD being genetic. The 1994 paper in the journal Neurology, in which I reviewed hundreds of medical records from the Boss’s PD families, helped to turn the tide of thinking toward a genetic component. When the Boss shared the extensive Contursi pedigree with the folks at NIH, and along with funding from the APDA, we began a collaboration that resulted in discovering the causative gene. A mutation in the alpha-synuclein gene, designated PARK1, was consistently inherited only in those family members who had PD.
It is now over 15 years and many millions of dollars later and we still don’t know exactly what alpha-synuclein does in the normal brain. However, we are making great progress in devising ways to counter its effects in the parkinsonian brain, progress that might not have been made without the vision of a man who had the tenacity of a salmon swimming upstream.
As a PD patient, my heart sank to learn that the faulty alpha-synuclein replicates itself, spreading from cell to cell. I was buoyed, however, when the research team of Drs. Virginia Lee and John Trojanowski demonstrated that a specially formulated antibody can work outside a diseased cell to neutralize this effect, and that it not only prevented the spread of alpha-synuclein, but it improved symptoms in a mouse model of Parkinson’s. Now I am overjoyed to learn that AFFiRiS has demonstrated the safety of this approach in humans with a Phase 1 study, AND that they have early evidence to suggest symptomatic benefit in Parkinson’s patients.”
AFFiRiS is conducting a follow up study testing a boost vaccination, in Vienna, Austria starting in September 2014. To learn more about the PDO1A study see:
Dr. Alice Lazzarini:
Named a Top 20 Author of PD papers between 1996 and 2006, Dr. Alice Lazzarini raised a family as she trained to be a genetic counselor and then went on to finish her PhD at age 56. Her career has included 11 years coordinating a statewide program for Huntington disease families, contributing to the literature on neurogenetic disorders such as Huntington’s, Restless Legs the ataxias and Parkinson’s, and working on the development of a Parkinson’s drug for a large pharmaceutical company. She is publishing a memoir [Both Sides Now: A Journey From Researcher to Patient], about her experiences doing research at a time when The Human Genome Project was becoming a household word. You will enjoy Alice’s often-humorous perspective as she shares her personal journey from sheltered childhood to successful female scientist.
 Neurology 44:499-506, 1994
 Science 276:204507, 1997
 Cell Reports 7:2054-65, 2014
West Orange, 1942
I was 18-months-old when my parents moved into their suburban cape cod nestled in the Watchung mountains. Bragging her heroism—OR assuaging her guilt—my mother frequently told the story of having averted a near tragedy.
One sunny afternoon she had bundled me into my stroller for a daily afternoon’s walk. Then, descending a steep hill, she lost her footing and fell. As I hurled down the incline toward a busy intersection, she knew only that she had to cling to the stroller’s handle. Battered and bruised, knees bleeding, she saved me from certain disaster.
I have no recollection of that incident, but as age descends, I am aware of another free fall. Heretofore, insults to my body seemed easily fixable…
- Difficulty seeing? Simply get contacts.
- Injure one’s knee? Have arthroscopic knee repair.
- Trouble sleeping? Reduce your level of stress.
- Forget where you put your keys? You’ll remember momentarily.
The fixes are no longer simple…
- Difficulty seeing? I now need periodic injections to forestall the loss of my sight.
- Injure one’s knee? There’s no longer enough meniscus for a simple repair and likely requires complete replacement.
- Trouble sleeping? I invariably wake up at 2am, 3am, or 4am longing for the impossible respite of sleep.
- Forget where I put my keys? As my Parkinson disease worsens, I remember less and less.
And, where is that pretty young lady whose clutch kept me from careening into the dangerous intersection that lies below?
This article presents a very interesting finding, supported by multiple lines of evidence, helps tie in pesticides with the cellular biology of PD.
– “We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations, concentrations that were way below what was needed for the pesticides to do their job,”
– When ALDH does not detoxify DOPAL sufficiently, it accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.
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It is now over 16 years since my team reported the PD-causing role of a gene mutation, PARK1, in the alpha-synuclein protein (SNCA). So what have we learned since? If you do a search on PD and alpha-synuclein, you will get over 200,000 hits. Yet, here we are up to the discovery of PARK18 and still no miracle cure.
It turns out that the mutation in SNCA that we found in a large Italian family was originally introduced by Greek émigrés into Italy, but it remains a relatively infrequent cause of inherited PD. Then, in 2004, a mutation (PARK8) in the protein, leucine-rich repeat kinase 2 (LRKK2) was described and found to be a more common cause of PD. Known also as dardarin, LRKK2 can, like SNCA, form protein clumps inside brain cells.
But how do two disparate proteins cause a similar disease? Dr. Steven Finkbeiner’s group at Gladstone Institute of Neurological Disease at UCSF has begun to decipher this by using sophisticated imaging techniques to view the lifespan of single cells. Using cells from mice without SNCA and cells from PD patients with the most common LRKK2 mutation, they reported that the level of LRKK2 is what causes cell death, and that this level is dependent on SNCA.
Each of the steps that is clarified in the complicated pathway leading to PD opens new ways to approach potential treatment of this disease. Understanding the interaction of these two disparate PD-causing proteins, SNCA and LRKK2, is a very significant breakthrough that is key to clarifying that pathway.
For those of us who suffer from Parkinson disease, the hope is that these these findings bring us closer to developing effective treatment. As someone who was part of the team that set it in motion, I am excited to see a connection established between “our” gene and the more common mutation.