Mutant presenilin is infamous for its role in the most aggressive form of Alzheimer’s disease-early-onset familial Alzheimer’s-which can strike people as early as their 30s. In their latest study, researchers at the Salk Institute uncovered presenilin’s productive side: It helps embryonic motor neurons navigate the maze of chemical cues that pull, push and hem them in on their way to their proper targets.
"It provides a way of creating some of these intermediate temporal steps," explains postdoctoral researcher and first author Ge Bai. "It allows the use of a small number of genes to regulate axonal growth by regulating the signals’ effects in a very precise temporal and spatial ways."
He and his team found presenilin’s unexpected role in controlling the activity of axon guidance signals during a search for genes involved in the fetal development of the nervous system. They had developed a method of engineering mice so that all of their motor neurons glow green. This fluorescence allowed them to visually identify mutant mice that have errors in motor neuron development and function.
One mouse, whose specific defect the researchers had mapped to the gene coding for presenilin, stood out. Failing to exit the spinal cord, its motor neurons got stuck at the midline, a row of cells that lie, moat-like, in the middle of the developing embryo. Bai discovered that in presenilin mutant mice, they were irresistibly attracted to Netrin, which is expressed by the midline.
In normal mice, motor neurons turn a deaf ear to Netrin’s siren call and head out to the periphery. They are able to ignore Netrin because the receptor for Netrin is blocked by the so-called Slit/Robo tag team. Without presenilin, however, Netrin receptor fragments that are resistant to Slit/Robo silencing accumulate in the cell, and the motor neurons are now 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," says Bai.
Source: Salk Institute