Secondary Logo

Share this article on:

Christian Wider, MD — On Unraveling the Pathology of Perry Syndrome

STUMP, ELIZABETH

doi: 10.1097/01.NT.0000365681.41058.c1
DEPARTMENTS: UP&COMING

Swiss movement disorders neurologist Christian Wider, MD, hasn't wasted time while in the US these past three years. Now completing a three-year research fellowship in the genetics of neurodegenerative diseases at the Mayo Clinic in Jacksonville, FL, Dr. Wider received the AAN Jon Stolk Award in Movement Disorders for Young Investigators last April at the 2009 annual meeting, for his research on the pathophysiology of Perry syndrome, a familial condition characterized by early-onset parkinsonism, depression, weight loss, and hypoventilation.

Dr. Wider, a research fellow in neurology and neuroscience, earned his medical degree in 1998 and his doctorate in medicine (neurology) in 2006 from Lausanne University in Switzerland. He was the chief resident in movement disorders from 2004–2006 at Lausanne University Hospital. A member of both the Swiss Medical Federation and the AAN, Dr. Wider began his Mayo Clinic fellowship in 2006.

In an interview with Neurology Today, he discussed how he became interested in Perry syndrome and what research he anticipates doing in the future.

Back to Top | Article Outline

WHY DID YOU BECOME INTERESTED IN PERRY SYNDROME?

My clinical mentor at Mayo, Zbigniew Wszolek, had already been interested in Perry syndrome for years and had created an international consortium to study the clinical, genetic, and pathological characteristics of this devastating condition. Overall there are currently about 40 patients from 10 families who have already been reported or are currently affected by Perry syndrome, but investigators believe more families will eventually be identified and reported.

Through our international consortium we obtained eight brains donated by patients with Perry syndrome. Patients came from four families in Canada, the US, France, and Japan. I was fortunate to participate in the project when I began my fellowship.

Back to Top | Article Outline

TELL US MORE ABOUT THE RESEARCH PROBLEM AND RESULTS.

While severe neuronal loss in the substantia nigra had been reported before that accounts for parkinsonism, no specific inclusions had been identified in Perry syndrome. Neuronal or glial inclusions are a major feature of many neurodegenerative diseases such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia with tau (FTLD-T) or ubiquitin-positive (FTLD-U) inclusions. Identification of their protein content is crucial to formulate mechanistic hypotheses and to understand disease pathogenesis. Under the leadership of our neuropathologist Dennis Dickson, MD, we identified the pathological hallmark of Perry syndrome, the neuronal and glial inclusions that stain positive for the protein TDP-43 [TAR DNA binding protein 43].

Back to Top | Article Outline

WHAT DOES THE DISCOVERY MEAN FOR THE FIELD?

This discovery has two major implications. First, TDP-43 has recently been identified as the main protein content of inclusions in two other neurodegenerative diseases — FTLD-U and ALS, and the inclusions are morphologically similar to those found in Perry syndrome. However, the distribution is specific to Perry syndrome where, in contrast to FTLD-U and ALS, there is pallidonigral predominance with complete sparing of cortex, hippocampus, and motor neurons. The reasons behind this regional selectivity will need to be addressed in future studies. Second, the presence of TDP-43-positive inclusions raises the possibility that TDP-43 plays a role in the molecular cascade that leads to neurodegeneration in Perry syndrome, opening new research avenues.

Back to Top | Article Outline

WHAT ARE THE NEXT STEPS IN THE RESEARCH?

The first important step was to identify the genetic cause of Perry syndrome. The effort led by Mayo molecular geneticist Matthew Farrer, PhD, was successful with the rapid identification of mutations in the dynactin gene (DCTN1) in all available families with Perry syndrome. So we were fortunate enough, over only a few years, to have identified the pathological hallmark of the disease as well as its genetic cause.

These exciting discoveries led us to hypothesize that there might be a link between mutations in DCTN1 and accumulation of TDP-43. We are currently trying to understand the link between DCTN1 mutations, TDP-43 accumulation, neuronal loss, and clinical symptoms; and also the reason for selective neuronal vulnerability — that is, the reason why a mutation in one gene (DCTN1), which is present in all cells/neurons, only induces neuronal loss/death in restricted brain areas (mostly pallidonigral distribution in Perry syndrome).

Back to Top | Article Outline

WHAT ARE THE BENEFITS OF WORKING ON AN ORPHAN DISEASE LIKE PERRY SYNDROME?

Research on orphan diseases can be challenging because of limited patient availability and difficulty in obtaining funding. However, it has been very fulfilling in the case of Perry syndrome, because there is significant clinical, genetic, and pathological overlap with more common neurodegenerative diseases such as Parkinson disease. Therefore, unraveling the mechanisms implicated in neuronal loss in Perry syndrome may be relevant also to patients with more common diseases, and may contribute to the development of future strategies aimed at disease prevention and cure.

Back to Top | Article Outline

WHO WOULD YOU CITE AS MENTORS FOR YOUR WORK?

The multidisciplinary nature of this project has given me the tremendous opportunity to be mentored by three exceptional researchers at the Mayo Clinic Jacksonville: Zbigniew Wszolek, MD (movement disorders neurologist), Dr. Dennis Dickson, and Dr. Matthew Farrer.

Back to Top | Article Outline

WHAT ARE YOU WORKING ON NOW?

I am studying genetic factors implicated in Parkinson disease, using family-based molecular genetic/linkage studies and population-based association studies. I will soon return to my home institution in Lausanne, where I will pursue research in genetics of neurodegenerative diseases. However, I will keep an appointment at the Mayo for one more year as a research collaborator.

Back to Top | Article Outline

NEW COLUMN ON EMERGING INVESTIGATORS

Up & Coming features younger investigators who are making inroads in basic and clinical neurology research. Send your ideas for future features on young investigators making a difference in the field to neurotoday@lwwny.com.

©2009 American Academy of Neurology