What can eight families, unrelated and spread around the globe inform the scientific community about maladies that span parkinsonism, uncontrolled weight loss, severe depression, breathing problems and sleep difficulties? Potentially, a great deal. Family members with these symptoms were diagnosed with Perry syndrome, a rare and familial form of Parkinson’s disease first described in 1975. Most patients with Perry syndrome die within 10 years of diagnosis, either from suicidal depression or neurological deficits and severe weight loss followed by a decline in lung function. To date, the syndrome has been recognized in nine families from Canada, England, France, Japan, Turkey and the United States.

A Mayo research team and their international collaborators, led by molecular neuroscientist Matthew Farrer, Ph.D., reported in the February issue of Nature Genetics that people with Perry syndrome have a mutation in a subunit of the dynactin complex (DCTN1; p150^glued). Eight of the nine known affected families provided the key to the discovery. The gene codes for proteins that help, serve as a vital molecular motor for a transport system. The Perry syndrome mutation suggests that cargo was being driven on a “train” that essentially had faulty brakes. Scientists hypothesize that moving freight, such as molecules, vesicles and organelles, on a network of crisscrossing microtubule “tracks” is vital for normal cell function, perhaps especially in neurons that can be dramatically elongated. Those with “faulty brakes” end up with depression and movement disorder.

“This is an attractive idea that makes sense to us, but it is still a hypothesis that needs to be tested,” says Dr, Farrer, whose lab is located in the Udall Center of Excellence in Parkinson’s Disease Research at Mayo’s Florida campus.

Projecting impact beyond the rare disease

What excites the researchers is that the mutations they tracked are very close to mutations in the same gene found in a family with slowly progessing amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) — just 12 amino acid units away. Scientists have noted disruptions in this railroad system in many forms of neurodegeneration but have dismissed them as a consequence of the disorder. If trafficking of specific cargoes inside brain cells turn out to be a general problem in a variety of degenerative brain diseases and depression, that would be an important discovery.

It points us to a unified theory of what is going wrong in many of them,” says the study’s senior author, Zbiginiew Wszolek, M.D.

Understanding why distinct brain cells are selectively vulnerable to degeneration in different brain disorders is one of the greatest puzzles in neuroscience.

“In some forms of Parkinson’s disease, growing evidence indicates that the cargoes being trafficked are also misdirected by faulty signaling due to pathogenic mutations in a gene called leucine–rich repeat kinase 2(LRRK2),” says Dr. Farrer.

A seven–year, global quest for patient samples

It was a jaw–dropping moment for the researchers in May 2008 when they found the gene mutation, especially since it came after a sustained international effort to find Perry syndrome patients. Perry syndrome is autosomal dominant, meaning that the chance of inheriting it is 50 percent — one parent passes down the abnormal gene. Dr. Wszolek has been forging alliances with scientists worldwide since 1987.

“It took seven years to collect the critical mass of patients and their families, blood samples, and brain tissue from autopsies,” says Dr. Wszolek. “It was a painstaking and very devoted effort. At any meeting I speak at, I always ask at the end if anyone knows of a patient with this or that very rare syndrome. I have made my career building international collaborations.”

Dr. Wszolek’s contact with a Japanese researcher led to discovery of a family with Perry syndrome and the eventual donation of a deceased patient’s brain to the Mayo brain bank. In it, pathologists found only about 30 percent of neurons responsible for depression and pulmonary function intact. In addition, although they appeared in a different location to other disorders, lesions similar to ALS and rare forms of dementia filled parts of the brain.

Information from eight of the nine known families was included in the studies. It was a culmination of research from six countries, led by the Mayo team, that resulted in a number of publications about Perry syndrome, ultimately leading to the finding that the disease is due to five novel mutations in the DCTN1 gene (Nat Genet. Feb 4, 2009).

In the meantime, other Mayo scientists had contributed significant knowledge. Mayo neurologist Eduardo Benarroch, M.D., was first to describe the loss of neurons in critical brain stem regions and brain pathologist Dennis Dickson, M.D., first detailed characteristic aggregates within surviving cells in brains of patients diagnosed with Perry syndrome.

Digging deeper with a molecular tool kit

Now that all the clinical features of the disorder have been described, along with the pathology and the genetic cause, Dr. Wszolek believes that the illness should be called Perry disease, instead of Perry syndrome. However, that is a semantic change that he realizes won’t help patients.

“Despite all our work, there is little we can do in the near future for them,” says Dr. Wszolek. “However, knowing the existence of a Perry disease gene will most likely help to identify more patients and therefore establish a wider base for future research.”

There are many questions to be answered and other factors to investigate. Different brain cells might be affected in different diseases when protein interaction is affected by mutant dynactin.

“We are finding all these errant genes and proteins, but we don’t know how they interact with each other, what they do, how they produce cell death,” says Dr. Wszolek. “But it is fascinating. How can mutations in a single gene, only several base pairs apart, produce different brain diseases? And how can that also produce profound depression, sleeplessness and breathing problems?”

Dr. Farrer is anxious to answer those questions.

“What we have now is a molecular tool kit,” he says. “We can look at neurons with and without the mutation to find cause and effect. Eventually we hope that novel therapies will be developed from these molecular insights to help patients with Perry disease and perhaps related disorders such as Parkinson’s disease and Lou Gehrig’s disease.”

Dr. Wszolek notes. “It took 100 years to study bacteria responsible for pneumonia and develop penicillin. I think we have a much quicker start on understanding Perry disease.”

— Renee Twombly, February 2009