Broken Signals Lead To Neurodegeneration

Neurogenerative diseases could be explained by modifications of the IP3 receptor which lock it in a closed state.

AsianScientist (Sep. 9, 2014) – Scientists have discovered that a cell receptor widely involved in intracellular calcium signaling can be locked into a closed state by enzyme action, and that this locking may potentially play a role in the reduction of neuron signaling seen in neurodegenerative diseases such as Huntington’s and Alzheimer’s disease.

In the research published in the Proceedings of the National Academy of Sciences, researchers from the RIKEN Brain Science Institute in Japan, in collaboration with Juntendo University and the Japan Science and Technology Agency reported that transglutaminase type 2—a protein cross-linking enzyme elevated in the cells of patients with neurodegenerative diseases—interacts with the IP3 receptor to lock it in a closed non-functional conformation, thereby preventing it from fulfilling its essential calcium-releasing role.

They identified a specific amino acid site on the receptor, Gln2746, where the modification takes place, deepening our understanding of how receptors are locked and potentially opening the door to studies on other functional proteins that are also regulated by conformational changes.

The IP3 receptor channel—located in the protein assembly and transport compartment of the cell known as the endoplasmic reticulum—plays a crucial role in intracellular calcium signaling. It is involved in a wide range of cell functions including mitochondrial energy production and the regulation of autophagy, the process through which cells consume and degrade unused components to maintain a healthy balance of functional proteins.

Although autophagy is normally sustains cell maintenance, it can also trigger a loss of cell function and has been associated with prominent diseases including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease.

In this work, the scientists propose a general model under which abnormal IP3 receptor-mediated calcium signaling caused by the action of transglutamase type 2 leads to cellular dysfunction and subsequently to the emergence of progressive brain dysfunction. Transglutaminase 2 activation is commonly associated with inflammation and stress, and its action on the IP3R channel might provide an explanation for the initiation and progression steps common to different neurodegenerative diseases.

According to Katsuhiko Mikoshiba, who led the study, “We think that the mechanism we identified in this study could provide us with a more general model of other diseases both of the brain and other parts of the body, where transglutaminase type 2 is upregulated. We hope that this insight could eventually lead to the development of new drug therapies for a number of neurodegenerative diseases that place a high burden on patients and society.”

The article can be found at: Hamada et al. (2014) Aberrant Calcium Signaling by Transglutaminase-Mediated Posttranslational Modification of Inositol 1,4,5-Trisphosphate Receptors.


Source: RIKEN.
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