Neuroscientists have long suspected that abnormal calcium signaling and accumulation of misfolded proteins cause an intracellular membrane-bound organelle called the endoplasmic reticulum (ER) to trigger the abnormal death of cells implicated in many neurodegenerative diseases. However, the underlying mechanisms have proved elusive.
The ER is crucial for synthesizing proteins and maintaining their quality, and also acts as a reservoir of calcium ions essential for numerous cellular events. However, it is sensitive to alterations of surrounding environments, causing a process called ER stress.
Katsuhiko Mikoshiba and Takayasu Higo at the RIKEN Brain Science Institute, Wako, and their colleagues now report that a calcium channel called IP3 receptor type1 (IP3R1), which mediates the release of calcium ions from ER, is destroyed by ER stress and that this induces neuronal cell death and brain damage (Fig. 1).
Using a calcium imaging technique, the researchers revealed that IP3R1 released less calcium in cultured neurons treated with an ER stress inducer than in controls. To investigate the significance of this dysfunction, they bred mice lacking the gene for IP3R1, which caused brain damage under ER stress conditions.
In an exploration into how ER stress impairs IP3R1 and induces neuronal cell death. Mikoshiba and colleagues identified GRP78, a molecular ‘chaperone’ that normally regulates the cellular response to misfolded proteins, as an interacting partner of IP3R1. RNA interference experiments revealed that GRP78 positively regulates the assembly of IP3R1, which consists of four subunits. They also found that this interaction was inhibited under ER stress conditions.
In a further set of experiments, the researchers then examined the involvement of the interaction in neurodegenerative diseases using a mouse model of Huntington’s disease (HD). They found that both the protein interaction and IP3R1 channel activity were significantly impaired in parts of the brain most affected in HD.
The findings demonstrate a novel mechanism by which ER stress impairs the regulation of IP3R1 by GRP78. Mikoshiba and Higo propose that IP3R1 functions to protect the brain against stress and that the link between ER stress, IP3/calcium signaling, and neuronal cell death is associated with neurodegenerative disease.
“It has been suggested that neurodegenerative conditions including Huntington’s disease are associated with deranged calcium signaling and ER stress,” says Mikoshiba. “We hypothesize that IP3R1 functions to protect the brain from ER stress, so development of a method to restore or enhance IP3R1 could prevent disease progression or alleviate the symptoms. Our findings might be applied to other neurodegenerative diseases such as Alzheimer's disease.”
The corresponding author for this highlight is based at the Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute
Journal information Higo, T., Hamada, K., Hisatsune, C., Nukina, N., Hashikawa, T., Hattori, M.,
gro-pr | Research asia research news
Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory
‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong
Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...
An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications
Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...
Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.
The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...
Transistors based on carbon nanostructures: what sounds like a futuristic dream could be reality in just a few years' time. An international research team working with Empa has now succeeded in producing nanotransistors from graphene ribbons that are only a few atoms wide, as reported in the current issue of the trade journal "Nature Communications."
Graphene ribbons that are only a few atoms wide, so-called graphene nanoribbons, have special electrical properties that make them promising candidates for the...
08.12.2017 | Event News
07.12.2017 | Event News
05.12.2017 | Event News
08.12.2017 | Life Sciences
08.12.2017 | Information Technology
08.12.2017 | Information Technology