New treatments for neurological disorders

Tuesday 1 November 2005

Otago research points to new treatments for neurological disorders
-University researchers discover new mechanism protecting motor neurons -

A major discovery about a protein’s previously unsuspected role in maintaining vital nerve cells in the brain may lead to new treatments for a range of debilitating neurological conditions, according to University of Otago researchers.

The Otago researchers’ findings, published today in one of the world’s leading science journals, may also offer new clues to gender-specific differences in such conditions and in male and female brains generally.

Until now, the only important role the protein, known as MIS, had been thought to play was in the development of the reproductive anatomy of male embryos, says Associate Professor Ian McLennan, who leads the University’s Neuromuscular Research Group in collaboration with Dr Kyoko Koishi.

“Our finding that the adult motor neurons of both sexes produce MIS, as well as the proteins that enable its use, indicates that it plays an important role in regulating these vital brain cells, without which we couldn’t move or breathe,” says Associate Professor McLennan.

The discovery that mature neurons respond to MIS raises the possibility that it can be used as a drug to treat some neurological conditions which are currently incurable, he says.

The University’s commercialisation company, Otago Innovation Ltd (OIL), has now filed a number of patents in areas relating to the discovery and is currently looking for industry partners to pursue possible treatments.

OIL Commercialisation Manager Hamish Findlay says “this is exciting technology with potential to bring huge clinical benefits”.

“There are, however, many years of research and trials to go before a treatment is available for any neurological disorder,” he added.

The research may also cause a rethink of current understandings on the different structure of male and female brains, says Associate Professor McLennan.

“We also discovered that MIS prevents embryonic motor neurons from dying, indicating that it could affect embryonic brain development. As only male embryos’ brains are exposed to the substance, this raises the possibility that some aspects of the male brain are a by-product of MIS, rather than of androgens such as testosterone,” he says.

The exploration of sexual differences in the brain is important, both to fully appreciate our biology and because there are unexplained differences in the ways that many neurological and psychiatric conditions affect males and females, he says.

The research, which was supported by the “blue-skies” Marsden Fund, appears in the November 1 issue of the prestigious Proceedings of the National Academy of Science (US) journal.

Background Notes to release

During the 1st week of November 2005, the Proceedings of the National Academy of Sciences (USA) will publish a paper from the Neuromuscular Research Group. The Proceedings is one of the most prestigious scientific journals, and one of the few to publish papers from all scientific disciplines.

The paper is entitled “Mullerian Inhibiting Substance Acts as a Novel Motor Neuron Survival Factor in vitro” and is authored by Pei-Yu Wang1, Kyoko Koishi1, Andrew B. McGeachie1, Michael Kimber1, David T. MacLaughlin2, Patricia K. Donahoe2 & Ian S. McLennan1. 1Neuromuscular Research Group, Department of Anatomy and Structural Biology, University of Otago and 2Massachusetts General Hospital, and Harvard Medical School.

General Background.
Motor neurons are the neurons that activate skeletal muscles, enabling us to move and to breathe.

Müllerian Inhibiting Substance (MIS) is a protein that belongs to the transforming growth factor-beta superfamily of proteins. Cells use this family of proteins to signal to each other, enabling them to co-operate to form tissues and/or to regulate the activities of spatially-separated portions of the body. Their roles are similar to protein hormones such as insulin.

MIS is a “famous” protein whose actions were thought to be limited to the reproductive system. Male and female embryos are initially morphologically identical. Male embryos have all of the precursors of female-specific tissues whereas females initially produce the precursors of male-specific structures. The development of male features is under the control of MIS and testosterone.

The brain is structurally the most complex tissue in the body. Its structure and function are created and regulated by inter-cellular regulators. The majority of the regulators have been identified and are being extensively studied due to their role in brain diseases. At least some of them are potential therapeutic agents for degenerative conditions of the brain and/or psychiatric conditions.

What have we found.
We have discovered that motor neurons in adult mice of both sexes produce MIS, as well as the proteins that enable them to respond to MIS. This implicates MIS as a new regulator of the adult brain, whose function possibly includes stimulating co-operation between neighbouring motor neurons.

We have also shown that MIS can prevent embryonic motor neurons from dying in vitro. This suggests that MIS is part of the mechanism that maintains the motor portions of the brain.

Why is this important.
The discovery that mature neurons may be responsive to MIS raises the possibility that MIS can be used as a drug to treat certain neurological conditions.

The role of MIS was thought to be limited to triggering the degeneration of the precursor of the uterus (womb), with all of the other male features being created under the control of testosterone. Our demonstration that MIS supports the survival of embryonic motor neurons (nerve cells) makes us wonder whether some aspects of the male brain are a by-product of MIS, rather than androgens such as testosterone.

The exploration of sexual differences in the brain is important, both to fully appreciate our biology and because there are unexplained gender-specific difference in the incidences of many neurological and psychiatric conditions.

ENDS

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