Faculty and Researchers with STS Interests - Profile

Randy Schekman
Professor, Department of Molecular and Cell Biology
University of California, Berkeley


Email: schekman@berkeley.edu

Familial forms of Alzheimer's disease (FAD) are promoted by mutations in at least three proteins that engage in the production of the amyloidogenic peptide (Abeta42) that characterizes neuritic plaques believed to be responsible for neurodegeneration. Abeta42 is the product of proteolysis of a type I membrane protein, amyloid precursor protein (APP), which is produced in a variety of tissues but which appears to generate amyloid only in the hippocampus and the amygdala. Proteolysis is facilitated by a complex called the gamma-secretase, one subunit of which, presenilin 1 (PS1) (and its homolog PS2), is implicated in unscheduled proteolysis of APP. Randy Schekman’s lab has initiated a study of the traffic of APP and PS1 using a cell-free vesicle budding reaction that recapitulates the first step in the transport of membrane proteins from the ER to the Golgi complex in mammalian cells. They find that mutations in PS1 retard the packaging of mutant PS1 and of wild type APP into transport vesicles. Their working hypothesis is that this delay in transport may potentiate the cleavage of APP in the ER leading to an accumulation of Abeta42 peptide in this intracellular location. The mechanism that restricts the accumulation of Abeta42 to nerve cells remains unexplained. He wishes to examine this pathway in normal and PS1 mutant-transfected human embryonic stem cells. They have already performed the basic experiment with mouse embryonic stem cells, but the mutant transgenes are of human origin, thus the homologous reaction will be more pertinent and potentially instructive. As more is learned about the differentiation of hESCs in vitro, it will be possible to examine the traffic of APP and PS1 in neuronal and other differentiated cell types derived from the hESCs. The hope is that such a line of investigation will illuminate neuronal specific aspects of the generation of amyloid.

Website: http://www.hhmi.org/research/investigators/schekman.html

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