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
Warming ponds could accelerate climate change
21.02.2017 | University of Exeter
An alternative to opioids? Compound from marine snail is potent pain reliever
21.02.2017 | University of Utah
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
21.02.2017 | Life Sciences
21.02.2017 | Life Sciences
21.02.2017 | Life Sciences