Huntington’s disease (HD) is a progressive neurodegenerative disease characterized primarily by involuntary movements. Inherited mutations in the huntingtin gene cause a stretch of glutamine residues in its associated protein, huntingtin, to increase in length, so that the mutant protein misfolds and accumulates within neurons. Neurologists believe that failure to clear aggregates of this misfolded protein is an underlying mechanism involved in the onset of HD.
Nerve cells can now be induced to destroy mutant huntingtin protein and reduce aggregate formation, according to the results of a study led by Nobuyuki Nukina of the RIKEN Brain Science Institute in Wako1. The researchers suggest that their approach could be used to effectively treat HD.
Nukina and colleagues used genetic engineering to construct a fusion protein consisting of two copies of polyglutamine binding peptide 1, which is known to bind mutant huntingtin and suppress its aggregation, and the binding regions of heat shock cognate protein 70 (HSC70), which is a ‘chaperone’ protein that targets the mutant huntingtin for destruction.
The researchers found that their construct inhibited the aggregation of mutant huntingtin in cultured cells by inducing a process called chaperone-mediated autophagy, which does not normally break down the misfolded proteins. They also observed that the fusion molecule bound to the mutant huntingtin, forming complexes with HSC70 that were recognized as abnormal and sent to a structure called the lysosome for degradation.
The construct was also effective in clearing aggregates of several other misfolded proteins, including ataxin1, which causes a neurodegenerative disease called spinocerebellar ataxia.
The researchers tested their construct in two strains of mice with HD symptoms. They injected viral vectors containing the construct into the striatum, a brain region that is involved in the control of movement and degenerates in HD patients.
When they examined the animals’ brains four weeks later, they found the construct widely distributed throughout the striatum in both mouse strains. Importantly, the fusion protein had significantly inhibited huntingtin aggregation compared to control mice. As well as reducing the number of aggregates, the construct reduced the average size of the remaining aggregates. The treatment also alleviated HD symptoms in the animals: their movements improved in a behavioral task, they lost less weight, and their survival rate increased.
“Genetic therapy for Huntington's is currently not possible because of the difficulties involved in delivering genes to the brain,” says Nukina, “so we would like to develop or find a compound that can bind to expanded glutamine tracts and HSC70.”
The corresponding author for this highlight is based at the Laboratory for Structural Neuropathology, RIKEN Brain Science Institute
1. Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosawa, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y. & Nukina, N. Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. Nature Biotechnology 28, 256–263 (2010)
gro-pr | Research asia research news
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Materials Sciences
05.12.2016 | Power and Electrical Engineering