Featured Research

from universities, journals, and other organizations

Understanding a protein's role in familial Alzheimer's disease

Date:
November 14, 2013
Source:
University of California, San Diego Health Sciences
Summary:
Researchers have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease, discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.

Researchers at the University of California, San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer's disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.

The findings, published online in the journal Cell Reports, could help elucidate the still-mysterious mechanisms of Alzheimer's disease and better inform development of effective drugs, said principal investigator Lawrence Goldstein, PhD, professor in the Departments of Cellular and Molecular Medicine and Neurosciences and director of the UC San Diego Stem Cell Program.

"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," said Goldstein, who is also director of the new Sanford Stem Cell Clinical Center at UC San Diego. "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."

Familial AD is a subset of early-onset Alzheimer's disease that is caused by inherited gene mutations. Most cases of Alzheimer's disease -- there are an estimated 5.2 million Americans with AD -- are sporadic and do not have a precise known cause, though age is a primary risk factor.

In their study, Goldstein and colleagues examined presenilin 1 (PS1), a protein that helps break down other proteins, which is a vital biological necessity for cells and for life. Most notably, PS1 is the catalytic or action-driving component of gamma-secretase, an enzyme that cleaves or splits type-1 transmembrane proteins used to transport cellular material from one side of a cell's membrane to the other, from inside to outside or vice versa.

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 Goldstein. But perhaps 20 percent 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.

The researchers achieved their unprecedented precision by generating differentiated, purified neurons from stem cells derived from noted biologist Craig Venter, whose genome was fully sequenced and released for public research use in 2007. The created neurons contained different alleles or forms of the mutated gene that produces PS1.

"We were able to investigate exactly how specific mutations and their frequency change the behavior of neurons," said Goldstein. "We took finely engineered cells that we knew and understood and then looked how a single mutation caused changes in the molecular scissors and what happened next."

To exclude potential off-target artifacts observed in previous genome editing work, study co-author Kun Zhang, PhD, 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.


Story Source:

The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Grace Woodruff, JessicaE. Young, FernandoJ. Martinez, Floyd Buen, Athurva Gore, Jennifer Kinaga, Zhe Li, ShaunaH. Yuan, Kun Zhang, LawrenceS.B. Goldstein. The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells. Cell Reports, 2013; DOI: 10.1016/j.celrep.2013.10.018

Cite This Page:

University of California, San Diego Health Sciences. "Understanding a protein's role in familial Alzheimer's disease." ScienceDaily. ScienceDaily, 14 November 2013. <www.sciencedaily.com/releases/2013/11/131114193205.htm>.
University of California, San Diego Health Sciences. (2013, November 14). Understanding a protein's role in familial Alzheimer's disease. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/2013/11/131114193205.htm
University of California, San Diego Health Sciences. "Understanding a protein's role in familial Alzheimer's disease." ScienceDaily. www.sciencedaily.com/releases/2013/11/131114193205.htm (accessed August 20, 2014).

Share This




More Mind & Brain News

Wednesday, August 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Researcher Testing on-Field Concussion Scanners

Researcher Testing on-Field Concussion Scanners

AP (Aug. 19, 2014) Four Texas high school football programs are trying out an experimental system designed to diagnose concussions on the field. The technology is in response to growing concern over head trauma in America's most watched sport. (Aug. 19) Video provided by AP
Powered by NewsLook.com
Kids' Drawings At Age 4 Linked To Intelligence At Age 14

Kids' Drawings At Age 4 Linked To Intelligence At Age 14

Newsy (Aug. 19, 2014) A study by King's College London says there's a link between how well kids draw at age 4 and how intelligent they are later in life. Video provided by Newsy
Powered by NewsLook.com
Mental, Neurological Disabilities Up 21% Among Kids

Mental, Neurological Disabilities Up 21% Among Kids

Newsy (Aug. 18, 2014) New numbers show a decade's worth of changes in the number of kids with disabilities. They suggest mental disabilities are up; physical ones are down. Video provided by Newsy
Powered by NewsLook.com
Fake Weed Wreaks Havoc In New Hampshire

Fake Weed Wreaks Havoc In New Hampshire

Newsy (Aug. 17, 2014) New Hampshire's governor declared a state of emergency after more than 40 overdoses of synthetic marijuana in one week throughout the state. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins