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

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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.

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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

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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.

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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.”

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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.”

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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!!

The Arizona Three

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!