New Causes For Neurodegeneration Discovered By U-M Scientists

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New Causes For Neurodegeneration Discovered By U-M Scientists

http://www.medicalnewstoday.com/articles/86708.php

The previous paper " Mutation of FIG4 causes neurodegeneration in the

pale tremor mouse and patients with CMT4J, " was published in Nature

on-line, June 17, 2007.

Diseases that cause neurons to break-down, such as Alzheimer's,

Multiple Sclerosis and Creutzfeldt-Jakob disease (Mad Cow Disease),

continue to be elusive to scientists and resistant to treatments.

A new finding from University of Michigan researchers demonstrates

an unpredicted link between a virtually unknown signaling molecule

and neuron health.

In a study released in PNAS, the journal of the National Academy of

Sciences this week, graduate student, Yanling Zhang, postdoctoral

fellow Sergey Zolov and Life Sciences Institute professor Lois

Weisman connect the loss of this molecule to massive

neurodegeneration in the brain.

The molecule PI(3,5)P2 is a lipid found in all cells at very low

levels. Lipids are a group of small organic compounds. While the

best studied lipids are fats, waxes and oils, PI3,5P2 is a member of

a unique class of lipids that signal the cell to perform special

tasks.

Weisman said it was surprising to find that PI(3,5)P2 plays a key

role in the survival of nervous system cells.

" In mice, lowered levels of PI(3,5)P2 leads to profound

neurodegeneration, " said Weisman. " It suggests that we have a good

place to look to find treatments for neurodegenerative diseases such

as Alzheimer's. "

Weisman, who is also professor of Cell & Developmental Biology at

the U-M Medical School and her colleagues, began from clues that

were hidden in a conserved genetic pathway in yeast (a pathway that

has remained the same in yeast, plants and humans over evolutionary

time). Studies in yeast showed that the enzyme that manufactures the

lipid is governed by the FIG4 and VAC14 genes, which exist in yeast,

mice and humans.

Working with two independently derived mouse models, Weisman's team

and collaborators including graduate student Clement Chow and

Professor Miriam Meisler of the Department of Human Genetics at the

U-M Medical School, reached the same conclusions in a pair of

important papers for neuroscience research.

Building on research from Meisler, a mouse geneticist, and Weisman,

a yeast geneticist, the collaborators published a paper in Nature,

July 5, 2007, showing that in mice, the FIG4 gene is required to

maintain normal levels of the signaling lipid and to maintain a

normal nervous system. Importantly, they found that human patients

with a very minor defect in their FIG4 genes had serious

neurological problems.

The signaling lipid PI(3,5)P2 (short for phosphatidylinositol 3,5-

bisphosphate) is part of a communication cascade that senses changes

outside the cell and promotes actions inside the cell to accommodate

to the changes.

Weisman's team found that mice missing the VAC14 gene, which encodes

a regulator of PI(3,5)P2 levels, suffer massive neurodegeneration

that looks nearly identical to the neurodegeneration seen in the

FIG4 mutant mice. In both cases the levels of PI(3,5)P2 are one half

of the normal levels. The fact that both mice have half the normal

levels of the lipid and also have the same neurodegenerative

problems provides evidence that there is a direct link between the

lipid and neuronal health.

The new findings indicate that when Vac14 is removed, the cell

bodies of many of the neurons appear to be empty spaces and the

brain takes on a spongiform appearance.

The paper appearing in the online version of the Proceedings of the

National Academy of Sciences October 22, 2007 is " Loss of Vac14, a

regulator of the signaling lipid phosphatidylinositol 3,5-

bisphosphate, results in neurodegeneration in mice, " by a team of

collaborators from U-M: Yanling Zhang, Sergey N. Zolov, Clement Y.

Chow, Shalom G. Slutsky, Randal J. Westrick, J. on,

Miriam H. Meisler, and Lois S. Weisman and the University of Iowa:

Simon C. , C. Piper, Baoli Yang, and athan J.

Nau.