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 damage1 (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 Huntingtons 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 Huntingtons 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.
Higo, T., et al. Mechanism of ER stress-induced brain damage by IP3 receptor. Neuron 68, 865878 (2010). www.cell.com/neuron/abstract/S0896-6273(10)00917-7