Hereditary Spastic Paraplegias

A new study proposes a mechanism for the hereditary spastic paraplegias. The study suggests that a gene is defective and a substance called atlastin is defective in sufferers. Without these things a protein cannot be produced that supports the endoplasmic reticulum. - BRH

FROM NERVE ROOTS TO PLANT ROOTS - RESEARCHERS ARE GAINING UNEXPECTED INSIGHTS INTO HEREDITARY SPASTIC PARAPLEGIA

U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Institute of Neurological Disorders and Stroke (NINDS)
Embargoed for Release: Thursday, August 6, 2009, Noon, EDT

CONTACT: Daniel Stimson, NINDS, 301-496-5751

FROM NERVE ROOTS TO PLANT ROOTS - RESEARCHERS ARE GAINING UNEXPECTED INSIGHTS INTO HEREDITARY SPASTIC PARAPLEGIA

Sprouting. Branching. Pruning. Neuroscientists have borrowed heavily from botanists to describe the way that neurons grow, but analogies between the growth of neurons and plants may be more than superficial. A new study from the National Institutes of Health and Harvard Medical School suggests that neurons and plant root cells may grow using a similar mechanism.

The research also sheds light on the hereditary spastic paraplegias (HSP), a group of inherited neurological disorders in which some of the longest neurons in the body fail to grow and function properly. The genes behind HSP and their roles inside neurons are poorly understood. However, the study suggests that several forms of HSP share an underlying defect with each other - and with abnormal root hair development in a plant widely used for agricultural research.

The strange implication is that the plant, Arabidopsis thaliana (mouse-ear cress), could prove useful for further research on HSP.

"This study provides us with valuable new insights that will stimulate research toward therapies for hereditary spastic paraplegias," says Craig Blackstone, M.D., Ph.D., an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS) and an HSP expert. Dr. Blackstone performed the study in collaboration with William Prinz, Ph.D., an investigator at the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Tom Rapoport, Ph.D., a Howard Hughes Medical Institute investigator and a professor of cell biology at Harvard Medical School.

HSP primarily affects corticospinal neurons, which extend projections called axons from the brain's cerebral cortex to the spinal cord. The longest corticospinal axons extend nearly all the way down the spinal cord - a distance up to about three feet - in order to control movement in the legs. In HSP, these long axons develop abnormally or they degenerate later in life, causing muscle stiffness and weakness in the legs. HSP exists in many forms in different families, and more than 40 genes have been implicated in the disease.

In the new study, published in Cell, the researchers propose that defects in the shaping of a subcellular structure known as the endoplasmic reticulum (ER) are a common cause of HSP. The ER - named for its reticulated (or net-like) shape - is a cellular factory, where molecules such as proteins and lipids that are vital to cell growth are made and packaged for shipping to various cellular destinations. The researchers theorize that in several forms of HSP, the ER loses its complex shape and is unable to support the growth or maintenance of long corticospinal axons.

Several years ago, other researchers showed that similar ER defects in Arabidopsis impair the growth of the plant's root hairs. These are wispy, microscopic projections that grow from the plant's individual root cells.

The new study focuses on a gene called atlastin. This gene is defective in about 10 percent of HSP cases, and in previous research, Dr. Blackstone's group showed that it has a role in axon growth. The new study reveals that the atlastin protein is necessary for maintaining the shape of the ER in mammalian cells, and that an analogous protein called Sey1p performs the same function in baker's yeast.

The researchers demonstrate that ER shaping defects have general relevance for HSP, by showing a connection between atlastin and a group of proteins known as the DP1 family. Years ago, Drs. Prinz and Rapoport reported that a yeast analog of DP1 regulates the shape of the ER in yeast. Meanwhile, others researchers had independently reported that mutations in REEP1, a member of the DP1 family, cause 3 percent to 8 percent of HSP cases. The new study shows that atlastin interacts physically with DP1 in mammalian cells, and that Sey1p (the yeast atlastin) interacts with the DP1 analog in yeast.

Finally, Dr. Blackstone's study notes that Arabidopsis has an analog of atlastin, called Root Hair Defective 3 (RHD3). Mutations affecting RHD3 cause the plant to grow short, wavy root hairs.

If this connection between axon growth and root hair growth withstands further study, Arabidopsis could be a useful tool for investigating mechanisms of HSP. Arabidopsis is easy to raise in the lab, and the short root hairs of the RHD3 mutant are easy to observe, compared to the growth defects in atlastin-deficient neurons and yeast. Dr. Blackstone hopes to collaborate with other researchers to initiate a search for genes and compounds that correct root hair development in the RHD3 mutant, which might provide valuable therapeutic insights into HSP.

(HTML version includes photo):

The photo caption is: Top: Rat cortical neurons. Bottom: Arabidopsis roots. Left side shows normal neurons and root hairs. Right side shows the effects of atlastin/RHD3 deficiency, with shortening of both and waviness of root hairs. Neuron images courtesy of Dr. Craig Blackstone, NINDS. Arabidopsis images courtesy of Dr. John Schiefelbein, University of Michigan, Ann Arbor.

Reference: Hu J, Shibata Y, Zhu P-P, Voss C, Rismanchi N, Prinz W, Rapoport TA, and Blackstone C. "A Class of Dynamin-Like GTPases Involved in the Generation of the Tubular ER Network." Cell, Vol. 138, August 7, 2009.

NINDS is the nation's primary supporter of biomedical research on the brain and nervous system. NIDDK conducts and supports basic and clinical research and research training on some of the most common, severe and disabling conditions affecting Americans. The Institute's research interests include: diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases.

DR. WILLIAM MATTHEW TAPPED TO LEAD NINDS OFFICE OF TRANSLATIONAL RESEARCH

This is interesting to me. I'd like to know why someone would leave the private research sector right now for an NIH job. What is the pay rate for each position? And will he really tap into patient advocacy groups? - BRH

DR. WILLIAM MATTHEW TAPPED TO LEAD NINDS OFFICE OF TRANSLATIONAL RESEARCH

U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Institute of Neurological Disorders and Stroke (NINDS)
For Immediate Release: Thursday, July 30, 2009

CONTACT: Margo Warren, NINDS, 301-496-5924,

DR. WILLIAM MATTHEW TAPPED TO LEAD NINDS OFFICE OF TRANSLATIONAL RESEARCH

The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, has named William D. Matthew, Ph.D., as director of its Office of Translational Research (OTR).

Dr. Matthew will lead the Institute's efforts to translate the results of laboratory research into treatments for neurological disorders. Dr. Matthew was formerly Vice President of R&D Partnering and Business Development at UCB, an international biopharmaceutical company based in Brussels. He holds a Ph.D. in biochemistry from the University of California, San Francisco (UCSF), and has served on the faculty of Harvard Medical School in Boston and Duke University Medical Center in Durham, N.C.

"Moving treatments for neurological disorders from the lab bench to the bedside is one of the most important missions of the NINDS and also our most formidable challenge," said Story C. Landis, Ph.D., director of NINDS. "Dr. Matthew's experience in academic research and in drug development -- and especially his ability to bridge those two worlds -- will energize and focus our translational research efforts."

An untold number of potential therapeutic drugs disappear into a critical gap between academia and industry. Academia is the main source of insights into the mechanisms of disease -- and hence insights into potential drug targets -- but few academic scientists have the means to develop a drug. Meanwhile, pharmaceutical companies have the resources to formulate a drug and test it in clinical trials, but they cannot invest in a drug without some sign of market value.

The NINDS OTR aims to close this gap and accelerate drug development for neurological disorders. The OTR replaces the NINDS Office of Technology Development, and will build on NINDS' existing programs in translational neuroscience research. Dr. Matthew was selected to lead the OTR because his career ranges from academic neuroscience research to all stages of the drug development process.

At the beginning of his career, Dr. Matthew helped pioneer the use of antibodies as tools for neuroscience research and as therapies for neurological disease. (Antibodies are a part of the body's immune defenses, and work by attaching to foreign cells and marking them for destruction.) As a doctoral student at UCSF, Dr. Matthew developed antibodies that could be used to isolate and characterize proteins inside nerve cells. In the early 1980s, as a professor at Harvard Medical School, he was among the first to develop antibodies that modulate the function of proteins critical for neural activity. Antibodies of this kind are now used to treat multiple sclerosis and are under investigation in patients with Alzheimer's disease.

In 1990, Dr. Matthew moved to Duke University Medical Center to help establish the Neurobiology Department, and in 1998, he became scientific director of The George and Jean Brumley Neonatal-Perinatal Research Institute within Duke's Department of Pediatrics. The Institute's primary mission is to "explore the basis for birth defects and neonatal injury of the brain and lungs and translate the findings into clinical practice."

In 2001, Dr. Matthew was recruited to Schwarz Pharma, a mid-sized German-based drug company. Dr. Matthew was integral to building Schwarz Biosciences, a new research and development division, which involved establishing the company's first research labs, as well as partnering with academic labs and with other pharmaceutical companies. Schwarz Pharma grew substantially over the next six years, and was acquired by UCB in 2007. During his tenure there, Schwarz Pharma developed three new drug products for the U.S. and European markets:

-- Neupro (rotigotine) - a skin patch for stable, continuous relief from the symptoms of Parkinson's disease.
-- Vimpat (lacosamide) - a drug for treatment-resistant epilepsy.
-- Toviaz (fesoterodine) - a drug for symptomatic relief from overactive bladder.

As director of NINDS OTR, Dr. Matthew will oversee several NINDS initiatives that support translational research. He also will play a key role in NIH-wide translational research initiatives. These include the NINDS Cooperative Program in Translational Research which funds the preclinical optimization and testing of lead compounds into new drugs, and the NINDS Anticonvulsant Screening Program which has played a pivotal role in the discovery and development of drugs for epilepsy, including Vimpat.

Dr. Matthew is looking forward to bringing his diverse experiences to NINDS. "In the time since I began my career, neuroscientists have gained key insights into many neurological disorders, and created many opportunities for new treatments. My goal is to tap into the unique strengths of researchers, physicians, patient advocacy groups, and industry and government leaders so that we can turn those opportunities into realities," he said.

The NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease - a burden borne by every age group, by every segment of society, by people all over the world. For more information about the NINDS Office of Translational Research, visit .

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .

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