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 An evolutionary heads-up – The brain size advantage
22.05.2015 | Veterinärmedizinische Universität Wien

nachricht Endocrine disrupting chemicals in baby teethers
21.05.2015 | Goethe-Universität Frankfurt am Main

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Kieler Forschende bauen die kleinsten Maschinen der Welt

Die DFG stellt Millionenförderung für die Entwicklung neuartiger Medikamente und Materialien an der Christian-Albrechts-Universität zu Kiel (CAU) bereit.

Großer Jubel an der Christian-Albrechts-Universität zu Kiel (CAU): Wie die Deutsche Forschungsgemeinschaft (DFG) heute (Donnerstag, 21. Mai) bekannt gab,...

Im Focus: Basler Physiker entwickeln Methode zur effizienten Signalübertragung aus Nanobauteilen

Physiker haben eine innovative Methode entwickelt, die den effizienten Einsatz von Nanobauteilen in elektronische Schaltkreisen ermöglichen könnte. Sie entwickelten dazu eine Anordnung, bei der ein Nanobauteil mit zwei elektrischen Leitern verbunden ist. Diese bewirken eine hocheffiziente Auskopplung des elektrischen Signals. Die Wissenschaftler vom Departement Physik und dem Swiss Nanoscience Institute der Universität Basel haben ihre Ergebnisse zusammen mit Kollegen der ETH Zürich in der Fachzeitschrift «Nature Communications» publiziert.

Elektronische Bauteile werden immer kleiner. In Forschungslabors werden bereits Bauelemente von wenigen Nanometern hergestellt, was ungefähr der Grösse von...

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: Phagen übertragen Antibiotikaresistenzen auf Bakterien – Nachweis auf Geflügelfleisch

Bakterien entwickeln immer häufiger Resistenzen gegenüber Antibiotika. Es gibt unterschiedliche Erklärungen dafür, wie diese Resistenzen in die Bakterien gelangen. Forschende der Vetmeduni Vienna fanden sogenannte Phagen auf Geflügelfleisch, die Antibiotikaresistenzen auf Bakterien übertragen können. Phagen sind Viren, die ausschließlich Bakterien infizieren können. Für Menschen sind sie unschädlich. Phagen könnten laut Studie jedoch zur Verbreitung von Antibiotikaresistenzen beitragen. Die Erkenntnisse sind nicht nur für die Lebensmittelproduktion sondern auch für die Medizin von Bedeutung. Die Studie wurde in der Fachzeitschrift Applied and Environmental Microbiology veröffentlicht.

Antibiotikaresistente Bakterien stellen weltweit ein bedeutendes Gesundheitsrisiko dar. Gängige Antibiotika sind bei der Behandlung von Infektionskrankheiten...

Im Focus: Die schreckliche Schönheit der Medusa

Astronomen haben mit dem Very Large Telescope der ESO in Chile das bisher detailgetreueste Bild vom Medusa-Nebel eingefangen, das je aufgenommen wurde. Als der Stern im Herzen dieses Nebels altersschwach wurde, hat er seine äußeren Schichten abgestoßen, aus denen sich diese farbenfrohe Wolke bildete. Das Bild lässt erahnen, welches endgültige Schicksal die Sonne einmal ereilen wird: Irgendwann wird aus ihr ebenfalls ein Objekt dieser Art werden.

Dieser wunderschöne Planetarische Nebel ist nach einer schrecklichen Kreatur aus der griechischen Mythologie benannt – der Gorgone Medusa. Er trägt auch die...

Alle Focus-News des Innovations-reports >>>

Anzeige

Anzeige

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

TU Darmstadt: Gipfel der Verschlüsselung - CROSSING-Konferenz am 1. und 2. Juni in Darmstadt

22.05.2015 | Veranstaltungen

Internationale neurowissenschaftliche Tagung

22.05.2015 | Veranstaltungen

Biokohle-Forscher tagen in Potsdam

21.05.2015 | Veranstaltungen

 
B2B-VideoLinks
Weitere VideoLinks >>>
Aktuelle Beiträge

Nanogefäß mit einer Perle aus Gold

22.05.2015 | Biowissenschaften Chemie

Ferngesteuerte Mikroschwimmer: Jülicher Physiker simulieren Bewegungen von Bakterien an Oberflächen

22.05.2015 | Physik Astronomie

Was Chromosomen im Innersten zusammenhält

22.05.2015 | Biowissenschaften Chemie