Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers discover system that reduces neurodegeneration in Huntington’s disease

25.07.2018

Mechanism that could reduce the toxic aggregation of huntingtin protein discovered / new therapies possible in the long run

The neuroscientist Dr David Vilchez and his team at CECAD, the University of Cologne’s Cluster of Excellence for Aging Research, have made an important step towards understanding the mechanisms that cause the neurodegenerative disorder Huntington’s disease.


The image shows a C.elegans model of Huntington’s disease under the microscope. When the scientists silence the protein UBR5, they see a dramatic increase in the number of toxic protein aggregates in

Credit: Seda Koyuncu and Isabel Saez

Particularly, they identified a system blocking the accumulation of toxin protein aggregates, which are responsible for neurodegeneration. The results have now been published in the journal ‘Nature Communications’.

Huntington’s disease is a neurodegenerative disorder that results in the death of brain cells, leading to uncontrolled body movement, loss of speech and psychosis. Mutations in the huntingtin gene cause the disease, resulting in the toxic aggregation of the huntingtin protein. The accumulation of these aggregates causes neurodegeneration and usually leads to the patient’s death within twenty years after the onset of the disease.

To examine the mechanisms underlying Huntington’s disease, Vilchez and his team used so-called induced pluripotent stem cells (iPSC) from Huntington’s disease patients, which are able to differentiate into any cell type, such as neurons.

Induced pluripotent stem cells derived from patients with Huntington’s disease exhibit a striking ability to avoid the accumulation of toxic protein aggregates, a hallmark of the disease. Even though iPSCs express the mutant gene responsible for Huntington’s disease, no aggregates were found.

The researchers identified a protein called UBR5 as a protective mechanism for the cells, promoting the degradation of mutant huntingtin. These findings can contribute to a better understanding of Huntington’s disease and could be a step stone to developing further treatment in patients.

The researchers screened immortal iPSCs from patients and derived neurons for differences in their ability to avoid mutant huntingtin aggregation. They found that huntingtin can be degraded by the cellular disposal system known as the proteasome. However, this system is defective in the neurons, which leads to the aberrant aggregation of the mutant huntingtin protein.

Vilchez and his team found that UBR5 is increased in pluripotent stem cells to accelerate the degradation of huntingtin in the cells. To examine the role of UBR5 in the regulation of the mutant huntingtin gene (HTT), they reduced the levels of UBR5 and could immediately see an accumulation of aggregated proteins in iPSCs. ‘This was striking to see’, says Vilchez. ‘From nothing, the cells went to huge amounts of aggregates.’

The authors went a step further and examined whether UBR5 also controls mutant huntingtin aggregation in Huntington’s disease organismal models. Indeed, they found that dysregulation of UBR5 results in a massive increase in the aggregation and neurotoxic effects in neurons. On the other hand, promoting UBR5 activity blocks mutant huntingtin aggregation in the Huntington’s disease models.

To test the specificity of the results, the researchers also kept an eye on other illnesses. ‘We also checked the mechanism in other neurodegenerative diseases like amyotrophic lateral sclerosis’, says Seda Koyuncu, a doctoral student working in Vilchez’s lab and a main author of the publication. ‘Our result is very specific to Huntington’s disease’, adds Dr Isabel Saez, another main author working with Vilchez at CECAD. Even though the results could be important for treatment and drug development, there is no therapy yet. ‘It’s not like you discover something new and then there is a cure, it’s more difficult – but in some years there might be a therapy’, Saez comments. Until then, more research needs to be done.

CECAD is the Cluster of Excellence at the University of Cologne and Cologne University Hospital conducting research on diseases associated with aging. Its six research areas cover a wide range of basic research on the causes and mechanisms of these diseases. David Vilchez is a Principal Investigator in Research Area B: ‘Disruptions in Protein Metabolism Cause Aging-Associated Diseases’. His research mainly focuses on protein homeostasis regulation in stem cells and aging.

Publication:
‘The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients’. Seda Koyuncu, Isabel Saez, Hyun Ju Lee, Ricardo Gutierrez-Garcia, Wojciech Pokrzywa, Azra Fatima, Thorsten Hoppe and David Vilchez. Nature Communications, volume 9, 23 July 2018, article number: 2886 (2018)
https://www.nature.com/articles/s41467-018-05320-3

Media Enquiries:
Dr David Vilchez
Principal Investigator/Junior Research Group Leader, CECAD Cologne
+49 221 478 84172
dvilchez@uni-koeln.de

Press and Communications Team:
Peter Kohl
+49 221 478-84043
pkohl@uni-koeln.de

Further information:
http://www.cecad.uni-koeln.de/home

Anneliese Odenthal | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht A novel synthetic antibody enables conditional “protein knockdown” in vertebrates
20.08.2018 | Technische Universität Dresden

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.

The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Quantum bugs, meet your new swatter

20.08.2018 | Information Technology

A novel synthetic antibody enables conditional “protein knockdown” in vertebrates

20.08.2018 | Life Sciences

Metamolds: Molding a mold

20.08.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>