Presenilin normally plays a role in Alzheimer's disease  (Source:
The protein presenilin helps navigate embryonic motor neurons within a network of chemical cues in order to make necessary connections to wire the nervous system

Salk Institute researchers have found that the protein presenilin, which is normally associated with Alzheimer's disease, has some good qualities to it after all. 

Samuel Pfaff, Ph.D., study leader and a professor in the Gene Expression Laboratory at the Salk Institute, along with Ge Bai, a postdoctoral researcher, and a team of scientists, have discovered that presenilin not only plays a role in Alzheimer's disease, but also has a good role in helping motor neurons navigate chemical cues when locating their appropriate targets. 

Presenilin is a protein that operates as part of the gamma-secretase complex, which severs the amyloid precursor protein. This leads to a build-up of beta amyloid fragments, and in Alzheimer's disease, these fragments develop insoluble, hard plaques. 

But presenilin is not always the villain within our bodily functions, as Pfaff and his team discovered. While searching for genes involved in the nervous system during fetal development, the researchers found that presenilin acts as an usher in guiding motor neurons to their proper destination during the embryonic stage. 

Normal development consists of trillions of neurons "reaching" for others with their long extensions, called axons, in an attempt to make a connection and wire the nervous system. Motor neurons have to travel a long distance to find their targets, and at many intersections along the way, chemical cues attract or repel the neurons in an attempt to guide them. While studying this process, Pfaff and his team found that axons "switch allegiances when they reach a critical junction," which allows a small number of genes to control axonal growth by regulating the cues' effects in spacial and temporal ways. The Salk Institute team discovered that presenilin plays the part in controlling axon guidance signals.

"Because of the vast number of neurons in the nervous system, ensuring that every single cell is on target creates more biological complexity than we can account for with the genetic information encoded in our genome," said Pfaff. "There are an estimated 100 trillion connections in our brain and only about 20,000 genes."

Pfaff proposed that abnormal presenilin might be a part of the cause of Alzheimer's disease in humans because this would cause a "deregulation" of guidance on the presenilin's part. 

To see if this was the case, the team used mouse models that were engineered to have their neurons glow green. The team was able to see which mutant mice had poorly developed motor neuron function. 

Pfaff engineered one mouse with a defect from the gene coding for presenilin, and found that motor neurons were unable to exit through the spine. Instead, they would get stuck at the midline, which is a row of cells in the middle of the embryo. Netrin, which is expressed by the midline, attracts neurons in presenilin mutant mice while the motor neurons in normal mice are able to ignore the Netrin's tempting calls because of a Slit/Robo tag team. This allows them to travel to the periphery. 

But without normal presenilin, Netrin receptor fragments that are not affected by the Slit/Robo tag team can build up within the cell and make motor neurons attracted to Netrin.

"The most satisfying thing we have learned about presenilin is that this is a component that is not directly involved in the detection of signals either as a ligand or a receptor, but functions as a very important regulator of their spatiotemporal activity," said Bai. 

This study was published in Cell.

"I'm an Internet expert too. It's all right to wire the industrial zone only, but there are many problems if other regions of the North are wired." -- North Korean Supreme Commander Kim Jong-il

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