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Alzheimer's and the Wheel


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Prof. Irith Ginzburg. Deleting parts of the map


It is generally assumed that human beings invented the wheel, but as Prof. Irith Ginzburg shows in an article published in the Journal of Neuroscience, wheel-borne carriages fitted on tracks and led by coachmen have always existed within us - in our nerve cells. This means of transportation accommodates a molecule called tau mRNA, a critical factor in the formation of "tangles."
Tangles are long chains whose main ingredient is a protein called tau. They are a hallmark of certain forms of Parkinson's disease and are one of the two essential defining characteristics of Alzheimer's disease. When tau forms tangles, it is being produced in excess. So knowing the basic mechanisms of tau is vital to understanding these diseases.
"Tau protein is essential for nerve cell growth," explains Ginzburg. "In normal cells, it is found primarily in the axon [the long projecting arm of nerve cells that transmits signals to and receives signals from other nerve cells]. However, in patients suffering from Alzheimer's and Parkinson's disease it forms "tangles" and can be found throughout the cell and not only in the axon."
Curious to find out why this was so, Ginzburg went to the core - the nerve cell's nucleus, containing all of the cell's genetic information. In 1996, she tracked down the gene responsible for tau production and pinpointed the gene "promoter," which regulates gene expression (the level of gene expression determines the amount of protein that will be produced). She thus zeroed in on the basic mechanism determining the level of tau production.
Ginzburg then went on to analyze tau mRNA, the messenger that conveys the "secret combination" for the proteins production to a "protein factory," where tau is built. She found that tau mRNA normally travels only to the axon. The reason: tau mRNA has a built-in map specifying where it's supposed to go. But what impedes tau mRNA's safe arrival at the axon in Alzheimer's and Parkinson's disease patients? This is not yet fully understood. A messenger with a map shouldn't have trouble reaching a fixed destination. Ginzburg suspected that a faulty vehicle might be involved.

She showed that tau mRNA is transported by a "wheel" that rolls from the nucleus to the axon, on microtubules (long "tubes" that are present in all cells). The wheel is composed of various proteins and latches onto tau mRNA's map. One of the proteins forming the wheel acts as a "conductor," guiding the whole complex to its destination.
Observing that the proteins bind to tau mRNA's map, Ginzburg decided to delete minute parts of the map until she found which part, when deleted, would prevent the vehicle from reaching the axon.
Since different parts of the map correspond to different binding proteins, deleting a specific part of the map in effect causes the deletion of a specific protein from the wheel. This was how Ginzburg found that when the wheel lacks a certain protein - one from the "elav" family of proteins - tau mRNA accumulates in the cell body, "on the road" to the axon. This finding could explain why tangles (which, as noted earlier, form as a result of excess production of tau) are scattered throughout the cell.
Another interesting effect of the deletion was noted: when tau mRNA did not reach the axon due to the absence of the elav protein, the development of axons was impaired. This serves as strong evidence that the elav protein and tau play a central role in the branching out of nerve cells critical for nerve cell communication.
Ginzburg also settled a hotly debated issue when she showed that some tau mRNA molecules continue to migrate throughout the axon. Until now, some scientists believed that all tau mRNA molecules reaching the protein factories at the beginning of the axon invariably stopped there. "The molecules that continue to migrate within the axon may act as "reserve" molecules," explains Ginzburg. "They station themselves near protein factories throughout the axon and await an additional signal to bring about the creation of the protein. Thus, in case of tau shortage, the cell can immediately produce more of the protein precisely where it is needed."

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