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Scientists Show For The First Time How Leprosy Bug Targets Peripheral Nerves

Date:
December 16, 1998
Source:
Rockefeller University
Summary:
A team of researchers, led by scientists from The Rockefeller University, have identified how the bacterium that causes leprosy targets the peripheral nerve, the crucial step leading to nerve damage in this disease. The findings, reported in the Dec. 11 issue of the journal Science, open a window on developing treatments for the prevention of nerve damage in leprosy and also for understanding the underlying mechanisms of early events of nerve damage in other neurodegenerative diseases such as muscular dystrophy, multiple sclerosis and various types of peripheral nerve diseases.

A team of researchers, led by scientists from The Rockefeller University, have identified how the bacterium that causes leprosy targets the peripheral nerve, the crucial step leading to nerve damage in this disease. The findings, reported in the Dec. 11 issue of the journal Science, open a window on developing treatments for the prevention of nerve damage in leprosy and also for understanding the underlying mechanisms of early events of nerve damage in other neurodegenerative diseases such as muscular dystrophy, multiple sclerosis and various types of peripheral nerve diseases.

"We have identified for the first time the exact cellular site that the leprosy-causing bacterium uses to attack peripheral nerves," says Anura Rambukkana, Ph.D., principal investigator of the study and a research associate in the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller. "Our findings point to a way of treating the disease in its early stages, before the immune response comes into play. More importantly, these findings have tremendous ramifications for the understanding of the early molecular events leading to the nerve damage of other neurodegenerative diseases."

The peripheral nervous system consists of all the nerves that fan out from the central nervous system and includes the muscles, skin and internal organs. During development, Schwann cells encase nerve fibers and wrap around the axon to form the myelin sheath. The myelin sheath enables the axon to greatly improve the reliability and speed of the electric impulse, much like insulation on electrical wires. When myelin is damaged, the nerve fibers are no longer insulated and nerve impulses cannot be conducted efficiently. In the peripheral nervous system, this Schwann cell-axon unit is surrounded by a protective layer called the basal lamina, which is secreted by the Schwann cells.

The basal lamina consists of molecules called laminin-2, which anchor to the Schwann cells via molecular hooks called laminin receptors and mediates cellular communications from the environment outside the cell to the Schwann. A molecule called dystroglycan, a component of a protein assembly called the dystrophin-glycoprotein complex, is one of the major laminin receptors of the Schwann cell. Dystroglycan exists in two subunits, the outer membrane alpha subunit and the transmembrane beta subunit. alpha-Dystroglycan interacts with laminin-2 in the basal lamina, while beta-dystroglycan binds to cytoskeletal proteins in the peripheral nerves.

In the Science paper, the researchers used a cell culture technique developed by co-author James Salzer, M.D., Ph.D., and his co-workers at New York University School of Medicine. They took axons of the sciatic nerve and Schwann cells from rats, and cultured them together.

Rambukkana and his colleagues found that Mycobacterium leprae (M. leprae), the bacterium that causes leprosy, uses the laminin-2-dystroglycan complex linkage to interact with the peripheral nervous system. The scientists also found that M. leprae uses a cell binding area of laminin-2, called the G domain, to attack the Schwann cells.

"The G domain of laminin-2 bridges the bacterium to the alpha-dystroglycan receptor, so we think this interaction is sufficient for the bacterial invasion of the Schwann cell," says Rambukkana. "Therefore this bug can be used as a model to dissect the neural dysfunction associated with this cellular pathway, because we know that the disturbance of laminin-dystroglycan linkage causes peripheral neuropathies."

Using this bacterium they also identified for the first time the site on the laminin-2 molecule that interacts with alpha-dystroglycan.

"This finding is very important because the primary cause of certain types of muscular dystrophies is the disruption of laminin-2-dystroglycan linkage," says Rambukkana.

Leprosy is a chronic bacterial infection that damages nerves, mainly in the limbs and facial area, and also leads to skin lesions. M. leprae is the only known bacterial pathogen that attacks the peripheral nervous system in humans, and the nerve damage it induces is by far the leading cause of peripheral nerve disease in the world. Characterized by a long incubation period-up to five years-leprosy damages peripheral nerves and muscle. However, the prominent clinical manifestation of leprosy is nerve damage, which is initially identified as a loss of sensation. Complications of leprosy arise from loss of all sensation in the hands and feet, to the extent that accidental burns or injuries are not noticed, which leads to extensive scarring or even loss of fingers or toes and facial disfiguration. Deformities brought about by nerve damage are largely responsible for the horror and dread of this disease.

Leprosy can be treated with multidrug therapy that kills most of the M. leprae in a few weeks. However, nerve function loss caused by M. leprae invasion of Schwann cells is irreversible.

The research reported in the Science paper, as well as subsequent research in this area, may lead to an understanding of the cellular mechanisms behind other neurological diseases, such as muscular dystrophy, and multiple sclerosis and other peripheral nerve diseases. In muscular dystrophies, particularly congenital muscular dystrophy, the expression of laminin-2 and its receptor dystroglycan is significantly diminished. This disturbs the linkage between extracellular laminin-2 and intracellular cytoskeleton through the dystroglycan receptor. This causes the dysfunction of both muscle and peripheral nerves.

"We believe that there are common pathogenic mechanisms involved in leprosy and other neuromuscular diseases, although the origins of these diseases are different," says Rambukkana.

Rambukkana's co-authors are Vincent A. Fischetti, Ph.D., professor and head of the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller, Hiroki Yamada, M.D., and Kevin P. Campbell, Ph.D., of the Howard Hughes Medical Institute at the University of Iowa College of Medicine; George Zanazzi, B.S., and Salzer of New York University School of Medicine; and Todd Mathus, Ph.D., and Peter D. Yurchenco, M.D., Ph.D., of Robert Wood Johnson Medical School.

This research was funded in part by grants from the United Nations Development Programme/World Bank/World Health Organization Special Program for Research in Tropical Diseases and the federal government's National Institutes of Health.


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Cite This Page:

Rockefeller University. "Scientists Show For The First Time How Leprosy Bug Targets Peripheral Nerves." ScienceDaily. ScienceDaily, 16 December 1998. <www.sciencedaily.com/releases/1998/12/981216080332.htm>.
Rockefeller University. (1998, December 16). Scientists Show For The First Time How Leprosy Bug Targets Peripheral Nerves. ScienceDaily. Retrieved October 22, 2014 from www.sciencedaily.com/releases/1998/12/981216080332.htm
Rockefeller University. "Scientists Show For The First Time How Leprosy Bug Targets Peripheral Nerves." ScienceDaily. www.sciencedaily.com/releases/1998/12/981216080332.htm (accessed October 22, 2014).

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