“The Big Kahuna” and a Potential New Treatment for Parkinson Disease


At the 2016 World Parkinson Congress (WPC 2016) in Portland Oregon, I introduced alpha-synuclein as “The Big Kahuna.” It is the protein for which we found the first PD-causing gene mutation in a large family from Contursi, Italy, a small village southeast of Naples. That was 20 years ago, and alpha-synuclein continues to be the dominant player in understanding the disease process.

We’ve known for a while that PD pathology progresses as alpha-synuclein spreads from cell to cell. Recently, a team of researchers from Johns Hopkins University School of Medicine published a landmark paper in Science identifying the role of the lymphocyte-activation gene (LAG3) protein in perpetuating that spread of alpha-synuclein between cells. LAG3 binds to the pathological alpha-synuclein and facilitates its entry into neighboring cells. PD mice engineered to lack LAG3 had delayed loss of critical dopamine neurons as well as delay of behavioral difficulties. LAG3 reduction of PD pathology thus provides a new therapeutic target to slow the progression of Parkinson’s.

The good news is that LAG3 inhibitors are already being used in the burgeoning field of cancer immunotherapy. Cancer cells hijack the body’s natural defense by inhibiting activation of the very cells that attack it. LAG3 is one of a class of “immune checkpoint inhibitors” that do this by blocking cell-to-cell interaction. Using antibodies against LAG3 has thus proven promising for treating various cancers and if, it proves effective in delaying PD in humans, might be fast-tracked for approval.


At Thursday’s Wrap up session of (WPC 2016) an audience member expressed confusion over whether alpha-synuclein was a gene or a protein. “Both,” I answered using the analogy of an old fashion tissue dress pattern. If you make even a tiny change in that dress pattern, the final dress will reflect that change. Both the pattern and the final product can be called “dress.” Similarly, mutations, or changes in a gene affect the resultant protein and both the gene and the protein are referred to as “alpha-synuclein.”

Go Ask Alice


Go Ask Alice!

A Potential Test for Parkinson Disease Discovered by Scottish Researchers!

It is just twenty years since I stood on the top of a mountain in a small village southeast of Naples, Italy. In my arms I clutched blood samples that were destined to revolutionize the course of research for Parkinson disease (PD). Those samples would lead us to discover that a change in the gene coding for the protein alpha-synuclein was sufficient to cause PD. We soon learned that alpha-synuclein clumps in everyone with PD, whether or not there is a known mutation in the gene.

How fitting that this anniversary be marked by a team from the University of Edinburgh and the University of Oxford announcing the development of an assay to diagnose PD using alpha-synuclein. Previous attempts at measuring the protein have been notably unreliable, but this assay actually measures the ability of an individual’s alpha-synuclein to cause clumping.

The best shot we have at bringing an end to Parkinson’s is being able to test potential neuroprotective therapies early in the disease process. However, the confounding symptoms that constitute early PD can make diagnosis difficult. In the early stages of the disease, a large number of false diagnoses could lead to erroneous results and the possibility of missing a truly effective treatment.

This test, developed by Fairfoul, et al. and published on August 28th ahead of print in the Annals of Clinical and Translational Neurology, was able to differentiate alpha-synucleinopathies: Parkinson disease (PD), dementia with Lewy bodies (DLB), and even pre-symptomatic PD 100% of the time from healthy controls, from Alzheimer disease (AD), corticobasal degeneration (CBD), and Progressive Supranuclear palsy (PSP). If these results continue to hold up in a larger cohort, a way to more accurately identify Parkinson disease and related synucleopathies could be forthcoming.

Going to the World Parkinson Congress in Oregon?

Be sure to check out the Book Nook and come to my “Meet The Authors” session at 11:30 am on Wednesday, September 21st. I will share what it was like to develop Parkinson disease after having been part of one of the biggest breakthroughs in Parkinson’s research! I will be signing copies of my book, Both Sides Now, A Journey From Researcher to Patient, as well as giving out bookmarks and some fun campaign buttons.Twenty percent of the proceeds from Both Sides Now are donated to the American Parkinson Disease Association to support research and service to Parkinson’s families.

Continue reading

A Parkinson’s Songbird?

cropped-cropped-cropped-bothsidesnow-front-hires-08-231.jpgPeople ask why I have a picture of two overlapping zebra finches on the front cover of my book, Both Sides Now, A Journey From Researcher to Patient. I explain how terrified I have always been of birds, and how their role in providing researchers with an understanding of the pathways involved in Parkinson disease has changed my relationship with these tiny creatures. These male and female finches looking in opposite directions (Courtesy of the laboratory of Dr. Erich Jarvis at Duke) spoke to me of having seen Parkinson’s while looking from both sides of the white coat.

It’s been nearly 20 years since we reported the discovery that a single mutation in the gene for the protein alpha-synuclein caused Parkinson disease in a large family from a remote Italian village southeast of Naples called Contursi. We reported in our 1997 Science paper that all we knew about alpha-synuclein at the time was that “its equivalent protein in the zebra finch is thought to play a role in the process of song learning.”

In those 20 years, we’ve come a long way, with the Michael J. Fox Foundation now calling alpha-synuclein “the most promising target for a disease modifying therapy.” Millions of research dollars having gone into clarifying why it clumps into the Lewy bodies found in everyone with PD and into exploring different ways that we might counteract its detrimental effect.

In my book’s Postscript, Gone to the Birds… I tell of visiting the laboratory of Dr. Erich Jarvis, a neurobiologist and former dancer who studies the relationship between movement, song and the origin of language:

“I’d like to see a mutated alpha-synuclein gene inserted into a songbird,” I quipped to Dr. Jarvis, trying to envision what the results might be. I thought I had posed an impossible problem, as I couldn’t imagine the process of inserting a foreign gene into an embryo that had a protective eggshell.

“Oh, but we are trying to make transgenic zebra finches,’ he told me, reflecting on the work of his colleague Fernando Nottebohm at Rockefeller University…”

Now, researchers in Dr. Nottebohm’s lab report successfully inserting a disease gene into songbird eggs. “Finches provide clues for Huntington’s disease” read the headline from Medical News Today referring to a study published online 5 October 2015 (doi:10:10.1038/nn.4133) in which Liu et. al. created birds with both a motor and vocal disorder. A transgenic Parkinson disease bird should soon offer yet another tool for our development of therapeutic strategies.

Day of Hope at Overlook Hospital

I thoroughly enjoyed speaking at Dr. Roger Kurlan’s Day of Hope at Overlook Hospital on September 19th. I had a  few fun slides such as this “Genetics 101.”

lightbulb genetics

I used my “Big Kahuna” to emphasize that the Michael J. Fox Foundation calls our breakthrough in identifying alpha-synuclein the “most promising therapeutic target for Parkinson disease.”

Big Kahuna

I  began the talk with having chaired a London meeting of parkinsonologists even as I realized I was developing PD. Finding Michael J. Fox’s book at Harrod’s was a lifeline for me—I needed to know if I would ever again feel “lucky.”  Having reviewed some promising therapeutics in development, I concluded saying that I’m still working on getting to “Lucky,” but I HAVE gotten to “Hopeful.”

Hopeful Woman2

Countdown to Portland

MTHA Book signing—cropped

It’s not yet September 2015 and everyone is gearing up to September 2016 and the 4th World Parkinson Congress  (WPC) in Portland, Oregon.  Two fellow “Parkies,” Jon Palfreman and Dave Iverson, are launching a must-see, free, downloadable podcast series: Portland Countdown. Beginning  June 2nd, on the first Tuesday of every month they will interview a cross section of individuals about Parkinson’s. The aim of the series is to educate the community about this  high-level, non-denominational conference which gathers the scientists, persons with Parkinson’s (PwP), and their families to share the very latest information about Parkinson’s, from day to day management to the very latest research into treatments. I met  WPD Executive Director Elizabeth Pollar (“Eli”) at April’s Parkinson’s Unity Walk in Central Park and was so impressed with her “ya’all come” philosophy. With her work on the World Parkinson Congress (WPC), she unites the varied Parkinson disease factions—you go, Eli girl!

I’m excited just thinking about the potential for sharing information and, what Jon called in  The New York Times article, “The Bright Side of Parkinson’s.” I  hope to see all my old friends in Portland—AND, to make many new ones.

In the interim, I’ve been getting wonderful press coverage, the most recent, an article by Susan Livio in The Star-Ledger.

Media can be irresponsible!

In a Medical News post, the headline read, “Mexican researcher close to finding a cure for Parkinson’s disease.” Then the last sentence qualifies that it “could even act as a cure.”

Well, I’m as anxious for a cure as the next guy, and am excited with some recent developments, particularly as result from my team’s discovery of the first Parkinson’s mutation in alpha-synuclein—I’m even intrigued by the mechanism described in the article as I’ve long suspected calcium’s involvement. (I once served as a control for a study measuring intracellular calcium and was so “off the chart,” that I skewed the data terribly. It’s significance has sat in the back of my thoughts ever since I developed Parkinson’s 10 years ago.) So, I laude Caraveo and Lindquist clarifying a mechanism tied to calcium! 🙂

But, the headline here is rather an over-reaching claim, and a disservice to the PD community…Let’s hope it does pan out!!

Keynote Speaker at Arizona APDA Optimism Conference

Just returned from Arizona (read: NO SNOW!) where I was Keynote speaker on Sunday. March 15th for the First Annual Optimism Summit and Expo. Sponsored by the Arizona chapter of the American Parkinson Disease Association at the Westward Look Resort and Spa, it brought hundreds of Parkinson Disease individuals and families together for a weekend full of events planned to educate, entertain and help families find ways to manage their day-to-day lives. I found a lot to learn myself and made some wonderful new friends—kudos to Executive Director Sarah Jones and her team for pulling together such an ambitious program in just a few short months. Arizona’s PD families are indeed lucky!

Alpha-synuclein in the news again 😃

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.

First Steps Towards a Vaccine for Parkinson’s disease

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.[1] 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.[2]

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.[3]  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.

[1] Neurology 44:499-506, 1994
[2] Science 276:204507, 1997
[3] Cell Reports 7:2054-65, 2014

Parkinson Disease Free Fall

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?

UCLA researchers uncover how pesticides increase risk for Parkinson’s disease

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.

View original post 760 more words

SNCA and LRKK2 Interaction

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.

Biomarker Breakthrough

A multi-center collaborative study has just been published in the journal JAMA Neurology. Sponsored by the Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative, the researchers measured four proteins in the cerebrospinal fluid (CSF) of early, untreated Parkinson’s patients compared to healthy controls. The four proteins are alpha-synuclein, two types of tau, and beta-amyloid—of Alzheimer disease  fame.

The study showed a reduction in each of four proteins between PD patients and controls. However the difference measured is still too small to be used as a practical diagnostic test. What the study does provide is the first evidence for a biological basis for different types of Parkinson disease. Measurement of CSF proteins were shown to distinguish between PD patients with postural instability-gait disturbance-dominant and tremor-dominant PD.

So why is this important if it can’t be used currently to make a diagnosis?

  • First, it will further researcher’s efforts to define the biological basis for the disease.
  • It would also enable researchers to more accurately group patients for assessment of treatment protocols. In any research protocol—especially drug trials—one wants to compare apples to apples, lest a positive outcome be diluted out and overlooked.
  • It could point the way toward recognition of PD before the appearance of overt symptoms (by which time 70% of the dopamine cells are already lost). This would provide a window for earlier, more specific treatment opportunities once they become available.

I was particularly excited to see continued evidence for the role of tau in PD. With support from the American Parkinson Disease Association, I had published the first evidence of an association of PD with tau (Lazzarini, et al. 1997); (Golbe, et al. 2001).  Fourteen years later, a genome-wide association study continued to support a strong association with the MAPT/tau locus (Spencer, et al. 2011). The current study lends further credence to  a biological role for tau in PD.


Golbe, Lawrence I., et al. 2001
The tau A0 allele in Parkinson’s disease. Movement Disorders 16(3):442-447.

Lazzarini, A.M. , et al.1997   
Tau intronic polymorphism in Parkinson’s Disease and Progressive Supranuclear Palsy. Neurology 48:A427.

Spencer, C. C., et al. 2011
Dissection of the genetics of Parkinson’s disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet 20(2):345-53.

Could medications for high cholesterol protect against Parkinson disease (PD)?

Identifying patterns that are associated with Parkinson’s across large groups of patients—the study of epidemiology—can be confounded by many things. Health care systems in other countries like the single-payer, compulsory National Health Insurance program (NHI) implemented in Taiwan in 1995, provide a level of uniform data than is difficult to achieve in our country. A recent publication from Taiwan takes advantage of their NHI, in which over 98% of the population is enrolled, in order to shed light on the basic mechanisms of PD, and in turn on potential treatment. Parkinson’s and other neurodegenerative diseases have been thought to involve a cascade of inflammation in the brain so that inhibiting the inflammatory response may be a viable approach to therapy. Since the statin drugs that are used to treat elevated cholesterol have anti-inflammatory effects, and they have been shown to reduce alpha-synuclein aggregation in animal models, a Taiwanese team studied whether various statins could affect the risk for developing PD—i.e. could the statins be protective? Other such studies to date, using self-reporting and without the numbers of patients needed to separate out (control for) the effect of most factors that could skew the results, have been inconsistent. Lee, et al (Neurology, July 30, 2013) were able to collect information on the effect of discontinuing different statins while controlling for the accuracy of diagnosis and the co-occurrence of other diseases and drugs. They compared one class of lipophilic (fat-loving) statins to the class of hydrophilic (water-loving) statins. A significant protective effect was demonstrated only by the continued use of the lipophilic statins. Because these cross the blood-brain barrier more readily, and because the disease process starts long before symptoms appear, the authors postulate that a protective effect of lipophilic statins may exist at the level of the dopamine brain receptors rather than on the degeneration of dopamine neurons.

  • Should you switch to a llipophilic statin?
  • Should you self-administer statin-like drugs?
  • Would I be better off if I also had high cholesterol requiring that I take statins?

Of Course Not!

What we can take from this comprehensive study is the knowledge that competent researchers are chipping away at the mechanism by which cells die, and each piece that is added to the puzzle exposes a different view of the overall picture which will one day be revealed to us. KTF

Parkinson disease and Mad Cows

Irish Cows

Irish Cows

MAD COW DISEASE! The very name conjures a sort of “pastoral interruptus” in which cows lazily grazing on a grassy knoll are overtaken by a seizure-like episode, one by one succumbing and tipping over, their legs stiffly extended skyward. Dire warnings follow, lest the Bovine Spongiform Encephalitis get into the human food chain and cause a variant of Creutzfeldt-Jakob disease (vCJD).

In the early 1980’s Dr. Prusiner of UCSF described a unique disease mechanism whereby a normal brain protein misfolds, and the protein itself serves as an infectious agent in the absence of known pathogens like bacteria and viruses. He coined it the “prion” protein, derived from the words “proteinacious” and “infectious.” These infective prions literally cascade from cell to cell within the brain, acting as a template to guide the misfolding of additional proteins, which clump and hijack the normal functioning of cells leaving characteristic sponge-like holes in its wake.

Just as with Parkinson and Alzheimer diseases, some of the group of prion diseases are caused by a specific genetic change in the offending protein. Shortly after Dr. Prusiner’s won the 1997 Nobel Prize in Physiology or Medicine for his ground-breaking work, I saw a family in which several members had one of the known genetic variants of the disease. I remember feeling something akin to revulsion as I pondered what it must feel like to know something is spreading inside you, something that is impervious to an army of anti-infectious soldiers as well as to sterilization—a phenomenon not unlike the spread of cancer, I thought.

Recently, a similar self-propagating mechanism has been described for Parkinson disease in which misfolded alpha-synuclein spreads from cell to cell inducing a characteristic protein clumping. Coined “permissive templating,” it helps explain the less than stellar results from the 1990’s when cell transplants were used to replace the dopamine-deficient cells in Parkinson disease—the transplanted tissue ultimately became “infected” which defeated the purpose of the intricate procedure.

Well, now, that’s a bummer! Diagnosed with a Mad-Cow-like disease of my own and awaiting my turn at keeling skyward, the cascade occurring inside my brain, is more than disturbing!

But wait—one can always make a loaf of banana bread from a bunch of rotting bananas! A recent publication reports taking advantage of the new-found, prion-like status of Parkinson’s with a view toward treatment of both diseases. A German research group has used high-throughput screening and found a compound which prohibits formation of the pathological forms of both prion protein and alpha-synuclein {Wagner J, Ryazanov S, et al, Acta Neuropathol (2013) 125:795-813}.

Will this likely be the “magic bullet?” Perhaps not, but it opens yet one more approach to the repertoire of treatment advances which has resulted from our description of that first Parkinson disease-causing mutation in alpha-synuclein.