Mayo Clinic: Brain disorder suggests common mechanism may underlie many neurodegenerative diseases

January 12, 2009

JACKSONVILLE, Fla. - A Mayo Clinic-led international consortium has found a mechanism that may help explain Parkinson's and other neurological disorders.

Studying just eight families worldwide, the international team of researchers have discovered a genetic defect that results in profound depression and parkinsonism in a disorder known as Perry syndrome. Although this syndrome is exceedingly rare, the mechanism implicated in it may help explain the origins of a variety of neurodegenerative disorders, such as Parkinson's and amyotrophic lateral sclerosis diseases, and even common depression and sleep disorders that are also hallmarks of the disorder, the researchers say.

In the study, to be published in the February issue of Nature Genetics (online January 11), the researchers report that people with Perry syndrome have mutations in a subunit of the dynactin complex (DCTN1; p150glued), which is essential to the movement of molecular "cargo" inside brain cells, or neurons. In this case, the mutations meant that the cargo was being driven on a "train" that essentially had faulty brakes. And because Perry syndrome resembles many other neurodegenerative diseases, the findings suggest breakdowns along the cell's interior transportation grid may be a common mechanism underlying neurodegeneration.

"Understanding why distinct neurons are selectively vulnerable to neurodegeneration in different brain disorders is one of the greatest puzzles in neuroscience," says the study's lead investigator, Matthew J. Farrer, Ph.D., a professor of neuroscience at Mayo Clinic. "These findings suggest that trafficking of specific cargoes inside brain cells may be a general problem in a variety of neurodegenerative diseases, depression, and other disorders."

"It points us to a unified theory of what is going wrong in many of them," says the study's senior author, Zbigniew K. Wszolek, M.D., professor of neurology at Mayo Clinic.

Molecules, vesicles and organelles within a cell are constantly carried via a network of crisscrossing microtubules that act like the tracks of an elaborate railroad system. Because, for the most part, neurons do not regenerate or divide as do other cells in the body, trafficking cargo efficiently over the lifetime of a neuron is fundamentally important, says Dr. Farrer.

Disruptions in this railroad system have been seen in many neurodegenerative diseases, but these problems have been generally regarded as byproducts of the disorder rather than the cause, the researchers say. These new findings may change that view, they say.

For example, in amyotrophic lateral sclerosis (ALS), a motor neuron disease also known as Lou Gehrig's disease, the molecular motors (for example, dynein, dynactin and kinesin) that drive transport from distant nerve terminals to the cell body may become defective. 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 the leucine-rich repeat kinase 2(LRRK2) gene, Dr. Farrer says.

The findings may also shed light on other neurodegenerative disorders, the researchers say. In Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, for instance, the "spikes," comprised of microtubule associated protein tau (MAPT), that normally stabilize and secure these rails tend to fall apart.

This discovery would not have been possible without a consortium of international researchers including co-authors from Canada, France, Japan, Turkey, and the United Kingdom, says Dr. Wszolek, who established the collaborative network of scientists.

Perry syndrome was first described in two unrelated Canadian families in 1975. In a study published in 2007, Dr. Wszolek, along with Swiss neurologist and visiting fellow Christian Wider, M.D., summarized the clinical features of the disease, which include early-onset parkinsonism (stiffness, slowness and rigidity), depression, severe weight loss, and increasing difficulty in breathing. Once symptoms occur, typically in the patient's mid-40s, the disease is rapidly progressive and fatal.

In a subsequent study published in August 2008, the consortium reported that eight patients who died from the disease had substantial loss of neurons in the midbrain area known as the substantia nigra. They also found a molecular signature of Perry syndrome - "inclusions," or clumps, of a protein known as TDP-43 - which is found in patients with frontotemporal dementia or with motor neuron disease. What these clumps represent is not known, says co-author and neuropathologist Dennis Dickson, M.D. "But they are clearly a marker of the disease process in all of these disorders, suggesting a common process is perturbed," he says.

Mayo geneticists hypothesized that Perry syndrome may be caused by mutations within the same gene, even though families afflicted with this disorder are unrelated, and come from different continents. The disease is autosomal dominant, meaning that the chance of inheriting the disease is 50 percent if one parent carries a copy of a mutant gene. With the help and participation of eight families with Perry syndrome, the Mayo-led team set out to find the defective gene.

They determined that each family had one of five novel mutations in the DCTN1 gene, whose protein produces a large subunit of the dynactin complex known as p150glued. This protein is essential to the movement of cargo along the microtubule rails. "Curiously, the mutations all cluster in the p150glued cytoskeleton-associated protein glycine-rich domain and its 'GKNDG' binding motif," Dr. Farrer says. "This region acts like a parking brake, so Perry mutations in p150glued mean that this brake is affected. It would be analogous to driving that train with faulty brakes."

What amazed the researchers are the similarities that Perry syndrome shares with other neurodegenerative diseases. Perry mutations in DCTN1 are physically very close to a mutation previously reported in familial motor neuron disease, they say.

The deposits of TDP43 are also the same as found in motor neuron disease and in some forms of frontotemporal dementia, although they are in a different part of the brain. "With the discovery of mutations in Perry syndrome, researchers have a new means to explore the breakdown in the microtubule transport system in each of these diseases," says Dr. Farrer. "The insides of neurons are very dynamic. Molecules and organelles are constantly being moved to where they are needed, so it makes sense that these disorders, with aging, may be caused by a progressive breakdown in this transport system."

Understanding Perry syndrome may shed light on depression as well as metabolic syndromes, says Dr. Wszolek. Many of the patients have profound depression and about one-third of those commit suicide. Many of the patients also experience severe weight loss and sleep deprivation.

Mayo Clinic

---

---

	Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics by M. Flint Beal (Author), Anthony E. Lang (Author), Albert C. Ludolph (Author) Neurodegenerative diseases are major contributors to disability and disease, with Alzheimer's and Parkinson's diseases the most prevalent. This major reference reviews the rapidly advancing knowledge of pathogenesis and treatment of neurodegenerative diseases in the context of a comprehensive survey of each disease and its clinical features. The editors and contributors are among the leading experts in the field internationally. Covering basic science, diagnostic tools and therapeutic approaches, the book focuses on all aspects of neurodegenerative disease, including the normal aging process. The dementias, prion diseases, Parkinson's disease and atypical parkinsonisms, neurodegenerative ataxias, motor neuron diseases, degenerative diseases with chorea, iron and copper disorders, and...
	Molecular Mechanisms of Neurodegenerative Diseases (Contemporary Clinical Neuroscience) by Marie-Francoise Chesselet (Editor) Marie-Françoise Chesselet, MD, PhD, and a panel of leading researchers and neurologists from industry and academia critically review the most recent advances from different yet complementary points of view. Focusing on Alzheimer's, Parkinson's, and CAG triplet repeat diseases, the authors show how studies of cellular and genetically engineered animal models have enhanced our understanding of the molecular mechanisms of neurodegenerative diseases and may lead to new therapeutics. Topics include the role of Ab toxicity, glial cells, and inflammation in Alzheimer's disease; the formation of abnormal protein fragments across several diseases, the impact of dopamine and mitochondrial dysfunction on neurodegeneration. Authoritative and insightful, Molecular Mechanisms of Neurodegenerative...
	Neurodegenerative Diseases (Advances in Experimental Medicine and Biology) by Shamim I. Ahmad (Editor) The editor of this volume, having research interests in the field of ROS production and the damage to cellular systems, has identified a number of enzymes showing ·OH scavenging activities details of which are anticipated to be published in the near future as confirmatory experiments are awaited. It is hoped that the information presented in this book on NDs will stimulate both expert and novice researchers in the field with excellent overviews of the current status of research and pointers to future research goals. Clinicians, nurses as well as families and caregivers should also benefit from the material presented in handling and treating their specialised cases. Also the insights gained should be valuable for further understanding of the diseases at molecular levels and should lead to...
	Neurodegenerative Diseases: From Molecular Concepts to Therapeutic Targets by Rommy Von Bernhardi (Editor), Nibaldo C. Inestrosa (Editor) This book discusses in detail the different hypothesis and experimental evidence regarding the neurobiological mechanisms involved in neurodegenerative pathology, with an emphasis in Alzheimer's and Parkinson's disease. Since there are many hypotheses for neurodegenerative diseases, there is a real need for a comprehensive view, allowing for integration of the different views for the pathogenic mechanisms of the disease.
	Neural Transplantation in Neurodegenerative Disease: Current Status and New Directions by Wiley
	Protein Quality Control in Neurodegenerative Diseases (Research and Perspectives in Alzheimer's Disease) by Yves Christen (Editor) The health of the proteome depends upon protein quality control to regulate the proper synthesis, folding, translocation, and clearance of proteins. The cell is challenged constantly by environmental and physiological stress, aging, and the chronic expressions of disease associated misfolded proteins. Substantial evidence supports the hypothesis that the expression of damaged proteins initiates a cascade of molecular events that leads to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and other diseases of protein conformation.
	Protein Chaperones and Protection from Neurodegenerative Diseases (Wiley Series in Protein and Peptide Science) by Stephan N. Witt (Editor), Vladimir Uversky (Editor) How protein chaperones protect cells from neurodegenerative diseasesIncluding contributions from leading experts, Protein Chaperones and Protection from Neurodegenerative Diseases provides an in-depth exploration of how protein chaperones are involved in shielding cells from toxic aggregated or misfolded protein states that cause ALS, Parkinson's, and related diseases.Examining how different protein chaperones ameliorate the toxicity of proteins that are known to cause neurodegenerative damage, the book addresses both research and clinical perspectives on chaperone and anti-chaperone properties. The intersection of molecular chaperones and neurodegeneration is an intensely studied area, partly because of the potential for manipulating the expression of molecular chaperones to thwart the...
	MANAGEMENT OF PARKINSON'S DISEASE: Strategies, pitfalls, and future directions A concise overview of clinical diagnosis, current therapeutic options, and ... neurodegeneration. (Postgraduate Medicine) by JTE Multimedia As the population ages, the incidence of Parkinson's disease is likely to increase. Unfortunately, the diagnosis can be complex, and current treatment options offer symptomatic relief in many patients but no cure for the underlying neurodegeneration. In this article, Dr Hermanowicz offers a concise overview of possible etiologic factors, clinical features, treatment principles and practice, and new therapeutic approaches that may improve management of Parkinson's disease in the future. Original Publication Date: December 2001
	ADULTS WITH NEURODEGENERATIVE DISEASES: Occupational Therapy Practice Guidelines (Aota Practice Guidelines) by Susan Forwell (Author)
	Inflammation, Lifestyle and Chronic Diseases: The Silent Link (Oxidative Stress and Disease) by Bharat B. Aggarwal (Editor), Sunil Krishnan (Editor), Sushovan Guha (Editor) Oxidative stress and inflammation are among the most important factors of disease. Chronic infections, obesity, alcohol and tobacco usage, radiation, environmental pollutants, and high-calorie diets have been recognized as major risk factors for a variety of chronic diseases from cancer to metabolic diseases. All these risk factors are linked to chronic diseases through inflammation. While short-term, acute inflammation generated by the immune system serves a therapeutic role, chronic low-level inflammation that may persist "silently" for decades is responsible for chronic diseases. Inflammation, Lifestyle, and Chronic Diseases: The Silent Link describes the role of dysregulated inflammation in persistent and recurring diseases. It investigates links to lifestyle and presents research...