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.
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.
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.
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
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.
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."
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
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.
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.
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.