LA JOLLA, CAMutant presenilin is infamous for its role in the most aggressive form of Alzheimer's diseaseearly-onset familial Alzheimer'swhich 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. Without it, budding motor neurons misread their guidance signals and get stuck in the spinal cord.
By putting genes associated with Alzheimer's disease in a new light, their findings, published in the Jan. 7, 2011, issue of the journal Cell, reveal 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 Howard Hughes Medical Institute investigator Samuel Pfaff, Ph.D., a professor in the Gene Expression Laboratory, who led the study.
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.
Many embryonic guidance molecules persist in the adult central nervous system, where they participate in maintenance, repair and plasticity of neural circuits. "This could explain how a deregulation of guidance signaling by abnormal presenilin may play a role in the pathogenesis of Alzheimer's disease," proposes Pfaff.
The Salk study also adds an important new piece to the clockwork mechanism that guides growing nerve cells through the embryo and that depends as much on timing as on spatial accuracy. Understanding how axons find their destinations may help restore movement in people following spinal
|Contact: Gina Kirchweger|