Mutations of presenilin 1 (PS1) have been implicated in familial Alzheimer’s disease (AD), but their molecular-level implications have remained murky. One particularly vexing question prompted by these mutations is as follows: Do mutated versions of PS1 simply lose beneficial functions, or do they gain harmful functions?

Until recently, the question could not be answered, mainly because most studies have relied on overexpression in mouse and/or nonneuronal systems. Now, however, researchers have tried an alternative approach to resolve the issue. These researchers, based at the University of California, San Diego, generated differentiated, purified neurons from stem cells. Because these neurons reflected an allelic series of PS1 mutations, they allowed the scientists to investigate exactly how specific mutations and their frequency changed neuronal behavior.

Through rigorous analysis of the allelic series, the scientists discovered that simple loss of PS1 function did not contribute to familial AD. Instead, they found that mutations led to a gain in activity that was toxic to some, but not all, PS1 functions.

The researchers published the results of their study November 14 in Cell Reports, in an article entitled “The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells.” Commenting on the study, one of the article’s authors, Lawrence Goldstein, Ph.D., director of the UC San Diego Stem Cell Program, said, “In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD.”

“We were able to identify and assign precise limits on how a mutation works in familial AD. That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”

In their study, Dr. Goldstein and colleagues focused on PS1’s role as the catalytic core of gamma-secretase, an enzyme that cleaves or splits type-1 transmembrane proteins. Among the type-1 proteins cleaved by gamma-secretase is amyloid precursor protein or APP, whose function remains incompletely known. When APP is cleaved by gamma-secretase, peptide fragments called amyloid beta are created.

Some researchers believe the accumulation of certain kinds of amyloid beta may result in neuron-killing plaques in the brain, a consequence that has been strongly linked to the development of AD.

Ordinarily, the “molecular scissors” of PS1 do their cutting with no adverse effect, according to Dr. Goldstein. But perhaps 20% of the time, he said there are “bad cuts” that result in potentially harmful amyloid beta fragments. “Our research demonstrates very precisely that mutations in PS1 double the frequency of bad cuts,” he said.

To exclude potential off-target artifacts observed in previous genome editing work, study co-author Kun Zhang, Ph.D., associate professor in the department of bioengineering at UC San Diego, said he and colleagues used whole exome sequencing to compare the engineered cells with other control cells. They determined that their genome editing approach did not introduce any additional mutations.

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