Forum für Wissenschaft, Industrie und Wirtschaft

Hauptsponsoren:     3M 
Datenbankrecherche:

 

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

15.11.2013
Novel genomic approach reveals gene mutation isn't simple answer

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.

Co-authors include Grace Woodruff, Jessica E. Young, Fernando J. Martinez, Floyd Buen and Jennifer Kinaga, Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute for Engineering in Medicine, UCSD; Athurva Gore and Zhe Li, Department of Bioengineering, Institute for Genomic Medicine and Institute of Engineering in Medicine, UCSD; and Shauna H. Yuan, Department of Neurosciences, Institute of Genomic Medicine and Institute of Engineering in Medicine, UCSD.

Funding support for this research came, in part, from the California Institute of Regenerative Medicine, the National Institutes of Health and National Institutes of Aging (grant R01AG032180); and the A.P. Giannini Foundation for Medical Research.

Scott LaFee | EurekAlert!
Further information:
http://www.ucsd.edu

More articles from Life Sciences:

nachricht New mechanisms uncovered explaining frost tolerance in plants
26.09.2016 | Technische Universität München

nachricht Chains of nanogold – forged with atomic precision
23.09.2016 | Suomen Akatemia (Academy of Finland)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: Quantenboost für künstliche Intelligenz

Intelligente Maschinen, die selbständig lernen, gelten als Zukunftstrend. Forscher der Universität Innsbruck und des Joint Quantum Institute in Maryland, USA, loten nun in der Fachzeitschrift Physical Review Letters aus, wie Quantentechnologien dabei helfen können, die Methoden des maschinellen Lernens weiter zu verbessern.

In selbstfahrenden Autos, IBM's Watson oder Google's AlphaGo sind Computerprogramme am Werk, die aus Erfahrungen lernen können. Solche Maschinen werden im Zuge...

Im Focus: Synthese-chemischer Meilenstein: Neues Ferrocenium-Molekül entdeckt

Wissenschaftler der Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) haben zusammen mit Kollegen der Freien Universität Berlin ein neues Molekül entdeckt: Die Eisenverbindung in der seltenen Oxidationsstufe +4 gehört zu den Ferrocenen und ist äußerst schwierig zu synthetisieren.

Metallocene werden umgangssprachlich auch als Sandwichverbindungen bezeichnet. Sie bestehen aus zwei organischen ringförmigen Verbindungen, den...

Im Focus: Neue Entwicklungen in der Asphären-Messtechnik

Kompetenzzentrum Ultrapräzise Oberflächenbearbeitung (CC UPOB) lädt zum Expertentreffen im März 2017 ein

Ob in Weltraumteleskopen, deren Optiken trotz großer Abmessungen nanometergenau gefertigt sein müssen, in Handykameras oder in Endoskopen − Asphären kommen in...

Im Focus: Mit OLED Mikrodisplays in Datenbrillen zur verbesserten Mensch-Maschine-Interaktion

Das Fraunhofer-Institut für Organische Elektronik, Elektronenstrahl- und Plasmatechnik FEP arbeitet seit Jahren an verschiedenen Entwicklungen zu OLED-Mikrodisplays, die auf organischen Halbleitern basieren. Durch die Integration einer Bildsensorfunktion direkt im Mikrodisplay, lässt sich u.a. die Augenbewegung in Datenbrillen aufnehmen und zur Steuerung von Display-Inhalten nutzen. Das verbesserte Konzept wird erstmals auf der Augmented World Expo Europe (AWE), vom 18. – 19. Oktober 2016, in Berlin, Stand B25 vorgestellt.

„Augmented Reality“ (erweiterte Realität) und „Wearable Displays“ (tragbare Displays) sind Schlagworte, denen man mittlerweile fast täglich begegnet. Beide...

Alle Focus-News des Innovations-reports >>>

Anzeige

Anzeige

IHR
JOB & KARRIERE
SERVICE
im innovations-report
in Kooperation mit academics
Veranstaltungen

Ist Vergessen die Zukunft?

27.09.2016 | Veranstaltungen

Von der Probe zum digitalen Modell - MikroskopieTrends ´16

26.09.2016 | Veranstaltungen

300 Experten diskutieren auf größter Entrepreneurship-Konferenz im deutschsprachigen Raum

26.09.2016 | Veranstaltungen

 
B2B-VideoLinks
Weitere VideoLinks >>>
Aktuelle Beiträge

Prozessintegrierte Prüfung für das ultraschallunterstützte Rührreibschweißen

27.09.2016 | Maschinenbau

IAB-Arbeitsmarktbarometer: weiterhin positiver Ausblick

27.09.2016 | Wirtschaft Finanzen

HIV-Antikörper mit breiter Wirkung als Basis für einen Impfstoff

27.09.2016 | Biowissenschaften Chemie