Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists identify underlying molecular mechanisms of Alexander disease

26.11.2019

UNC School of Medicine researchers used human induced pluripotent stem cells and CRISPR/Cas9 gene editing to make important basic science discoveries about the molecular underpinnings of Alexander disease, a rare neurodegenerative condition

Scientists have known that genetic mutations leading to the production of a defective protein called GFAP cause Alexander disease (AxD), a debilitating neurodegenerative condition that can present during infancy, adolescence, or adulthood.


Immunofluorescence staining of Alexander Disease iPSC-astrocytes showing cell nuclei (white), cytoplasmic GFAP filaments (magenta), and perinuclear GFAP aggregates (green; marked by yellow arrowheads).

Credit: Lab of Natasha Snider, PhD, UNC School of Medicine

Many people with the rare condition die within the first few years, but some survive for several decades. Now, UNC School of Medicine researchers are learning about the differences in the underlying biology of patients with severe and milder forms of AxD.

Led by Natasha Snider, PhD, assistant professor of cell biology, an international group of scientists has discovered that the mutant form of GFAP undergoes different chemical modifications, depending on time of onset of symptoms.

Published in the online journal eLife, this research marks the first time scientists have been able to model very specific chemical changes to GFAP that occur inside the AxD brain using an in vitro system derived from AxD patient cells.

This is allowing Snider and colleagues to probe the details of how GFAP misfolding and accumulation alters cellular mechanics to lead to disease progression and death.

"We are now further investigating the enzymes responsible for the key reactions inside brain cells that lead to AxD," Snider said. "We believe our research findings may open the door to new drug development opportunities for researchers and ultimately new kinds of therapies for people with this terrible disease."

AxD is a leukodystrophy, a rare group of disorders of the nervous system that involve the destruction of myelin, the fatty sheath that insulates long connective nerve cells and promotes the necessary communication of electrical impulses throughout the nervous system. As myelin deteriorates in people with AxD or other types of leukodystrophy, the activities of the nervous system deteriorate as well.

Most cases of Alexander disease occur during infancy and involve myelin destruction. Babies with AxD have enlarged brains, and they experience seizures, stiffness in the arms and legs, and developmental delay. Sometimes, though, symptoms do not occur until later in childhood or even in adulthood, and in the absence of leukodystrophy, when symptoms include speech abnormalities, swallowing difficulties, seizures, and poor coordination.

Over time, abnormal protein deposits containing GFAP known as Rosenthal fibers accumulate in specialized cells called astrocytes, which support and nourish other cells in the brain and spinal cord.

Since 2011, Snider has been studying the mechanisms of GFAP accumulation with the hope of finding an existing drug or compound to help AxD patients and developing insights needed to create a new kind of therapy. GFAP forms intermediate filaments - structures that shape the 'skeleton' of astrocytes.

Toxic accumulation of GFAP that is incapable of forming a proper structure leads to astrocyte dysfunction, which harms surrounding neuronal and non-neuronal cells in AxD patients. Problems of GFAP accumulation in astrocytes have also been found in other diseases, such as giant axonal neuropathy and astrocytoma tumors.

For the eLife study, Snider and colleagues combined mass spectrometry-based proteomic analysis of AxD and non-AxD human brain tissue with induced pluripotent stem cells and CRISPR/Cas9 gene editing technology to connect the relevant disease phenotypes to the underlying cell biology.

This work illuminated key mechanisms involved in GFAP misfolding and revealed new markers of disease severity. For the first time, they made a clear molecular distinction between AxD children who die young and people who live for several decades.

Using the cell line model created by Rachel Battaglia, a graduate student in the Snider lab, in collaboration with Adriana Beltran, PhD, assistant professor of pharmacology at UNC, the team observed specific types of GFAP aggregates sequestered outside the misshapen membranes of cell nuclei. "This phenomenon had been observed previously in astrocytes of AxD patients," Snider said.

"But ours is the first demonstration of this phenomenon in a model cell line in the lab to help us probe how exactly GFAP accumulation affects other cellular organelles to cause disease." These findings also relate to published literature on other debilitating and fatal human diseases associated with defects in intermediate filament proteins that have similar functions to GFAP.

The next step is to use this new knowledge to see if these molecular markers of GFAP aggregation can be leveraged for the creation of new treatments to help people with Alexander Disease.

###

Researchers received funding from the National Institutes of Health, the University of North Carolina Department of Cell Biology and Physiology, the National Science Foundation, the United Leukodystrophy Foundation, and Elise's Corner Fund.

Mark Derewicz | EurekAlert!
Further information:
http://news.unchealthcare.org/news/2019/november/scientists-identify-underlying-molecular-mechanisms-of-alexander-disease
http://dx.doi.org/10.7554/eLife.47789

Further reports about: Astrocytes GFAP cell biology molecular mechanisms nervous system

More articles from Health and Medicine:

nachricht Study shows novel protein plays role in bacterial vaginosis
13.12.2019 | University of Arizona Health Sciences

nachricht Illinois team develops first of a kind in-vitro 3D neural tissue model
12.12.2019 | University of Illinois College of Engineering

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Virus multiplication in 3D

Vaccinia viruses serve as a vaccine against human smallpox and as the basis of new cancer therapies. Two studies now provide fascinating insights into their unusual propagation strategy at the atomic level.

For viruses to multiply, they usually need the support of the cells they infect. In many cases, only in their host’s nucleus can they find the machines,...

Im Focus: Cheers! Maxwell's electromagnetism extended to smaller scales

More than one hundred and fifty years have passed since the publication of James Clerk Maxwell's "A Dynamical Theory of the Electromagnetic Field" (1865). What would our lives be without this publication?

It is difficult to imagine, as this treatise revolutionized our fundamental understanding of electric fields, magnetic fields, and light. The twenty original...

Im Focus: Highly charged ion paves the way towards new physics

In a joint experimental and theoretical work performed at the Heidelberg Max Planck Institute for Nuclear Physics, an international team of physicists detected for the first time an orbital crossing in the highly charged ion Pr⁹⁺. Optical spectra were recorded employing an electron beam ion trap and analysed with the aid of atomic structure calculations. A proposed nHz-wide transition has been identified and its energy was determined with high precision. Theory predicts a very high sensitivity to new physics and extremely low susceptibility to external perturbations for this “clock line” making it a unique candidate for proposed precision studies.

Laser spectroscopy of neutral atoms and singly charged ions has reached astonishing precision by merit of a chain of technological advances during the past...

Im Focus: Ultrafast stimulated emission microscopy of single nanocrystals in Science

The ability to investigate the dynamics of single particle at the nano-scale and femtosecond level remained an unfathomed dream for years. It was not until the dawn of the 21st century that nanotechnology and femtoscience gradually merged together and the first ultrafast microscopy of individual quantum dots (QDs) and molecules was accomplished.

Ultrafast microscopy studies entirely rely on detecting nanoparticles or single molecules with luminescence techniques, which require efficient emitters to...

Im Focus: How to induce magnetism in graphene

Graphene, a two-dimensional structure made of carbon, is a material with excellent mechanical, electronic and optical properties. However, it did not seem suitable for magnetic applications. Together with international partners, Empa researchers have now succeeded in synthesizing a unique nanographene predicted in the 1970s, which conclusively demonstrates that carbon in very specific forms has magnetic properties that could permit future spintronic applications. The results have just been published in the renowned journal Nature Nanotechnology.

Depending on the shape and orientation of their edges, graphene nanostructures (also known as nanographenes) can have very different properties – for example,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

Supporting structures of wind turbines contribute to wind farm blockage effect

13.12.2019 | Physics and Astronomy

Chinese team makes nanoscopy breakthrough

13.12.2019 | Physics and Astronomy

Tiny quantum sensors watch materials transform under pressure

13.12.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>