A kinder, gentler presenilin
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. A new study by researchers in the lab of Samuel Pfaff, however, has revealed presenilin's beneficial 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. Without it, budding motor neurons misread their guidance signals and get stuck in the spinal cord.
Presenilin is a component of the enzyme gamma secretase, which cleaves the amyloid precursor protein, resulting in accumulation of beta amyloid fragments. In Alzheimer's, these fragments form hard, insoluble plaques, one of the hallmarks of the disease.
The study's findings, however, published in the journal Cell, put genes associated with Alzheimer's disease in a new light, revealing an important link between the formation of neural circuits and neurodegenerative disorders. "It was a bit of a surprise since we always thought about presenilin in the context of severing neuronal connections rather than wiring the nervous system during embryonic development," says Pfaff.
Many embryonic guidance molecules persist in the adult central nervous system, where they participate in maintenance, repair and plasticity of neural circuits. During normal development, trillions of neurons reach out for others with long, slender extensions to touch, connect and wire the budding nervous system. As the hair-like protrusions, called axons, grope around in the developing embryo, trying to find their proper targets, molecular ushers stationed along their path steer them in the right direction.
"[Presenilin] provides a way of creating some of these intermediate temporal steps," explains postdoctoral researcher Ge Bai. "It allows the use of a small number of genes to regulate axonal growth by regulating the signals' effects in very precise temporal and spatial ways."
"This could explain how a deregulation of guidance signaling by abnormal presenilin may play a role in the pathogenesis of Alzheimer's disease," adds Pfaff.
Understanding how axons find their destinations may also help restore movement in people following spinal cord injury, or in those with motor neuron diseases such as Lou Gehrig's disease, spinal muscle atrophy and post-polio syndrome.