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Untangling motor neuron disease: implications for other neurodegenerative conditions
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Defects in motor neurons lead to the devastating motor neuron diseases of which the most common human form is amyotrophic lateral sclerosis (ALS). A new study from scientists in the University of Wisconsin-Madison has identified a defect in production of the protein neurofilament-L (NF-L) as the cause of neurofilament tangles in the nerve fibres. These tangles interfere with transmission of signals to muscles, resulting in muscle paralysis. The study was published online on April 3 in the journal Cell Stem Cell.

In ALS, essential voluntary muscle activity such as speaking, walking, breathing, and swallowing is adversely affected. The disease causes paralysis and death. Motor neurons control muscles under normal circumstances, but in ALS, motor neurons lose the ability to relay signals from the brain to the muscles. It was recently discovered that a mutation in the Cu/Zn superoxide dismutase (SOD1) gene was present in some ALS patients.

Attempts by researchers to transfer the mutated gene to animals and identify drugs to treat those animals were not yielding useful results. The current study adopted a more fundamental approach by using induced pluripotent stem cells (iPSCs) from patients with the SOD1 mutation. This was achieved using skin cells from patients that were transformed into induced pluripotent stem cells and in turn, into motor neurons. These iPSCs can be used as "disease models," as they carry many of the same traits as their donor. Dr Su-Chun Zhang, senior author on the paper, explains that this approach had an advantage of the genetic approach which "can only study the results of a known disease-causing gene. With iPSC, you can take a cell from any patient, and grow up motor neurons that have ALS. That offers a new way to look at the basic disease pathology."

Using this approach, the research team identified neurofilament, a structure that transports chemicals and cellular subunits including neurotransmitters to the far reaches of the nerve cell, for example signalling the muscles to move. In particular, mutant SOD1 caused decreases in stability of the messenger RNA encoding NF-L and hence reduction in the proportion of NF-L in neurofilament. This in turn resulted ibn neurofilament aggregation and formation of tangles. These tangles block the nerve fibres, so that they malfunction and die.
This discovery may have far-reaching consequences beyond ALS. Dr Zhang explains: "Our discovery here is that the disease ALS is caused by misregulation of one step in the production of the neurofilament," but "very similar tangles" appear in Alzheimer's and Parkinson's diseases. "We got really excited at the idea that when you study ALS, you may be looking at the root of many neurodegenerative disorders."

The misregulation occurs very early in motor neuron development, making it the most likely cause of this disease. When the research team edited NF-L expression in the SOD1-mutant motor neurons, cells were returned to normal. Dr Zhang reports that scientists at the Small Molecule Screening and Synthesis Facility at UW-Madison are searching for ways to rescue the defective motor neurons by testing libraries of candidate drugs. He concludes: "This is exciting. We can put this into action right away. The basic research is now starting to pay off. With a disease like this, there is no time to waste."

Sources

Chen, H. et al. (2014) Modeling ALS with iPSCs Reveals that Mutant SOD1 Misregulates Neurofilament Balance in Motor Neurons. Cell Stem Cell, April 3rd; DOI: http://dx.doi.org/10.1016/j.stem.2014.02.004

Press release: University of Wisconsin-Madison; available at http://www.eurekalert.org/pub_releases/2...040114.php
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