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Introduction

In the research of neurodegenerative diseases, a general process of degeneration has become clear. It starts from mutation, followed by abnormality of protein structure, progresses to protein aggregation, continues to cell dysfunction, and ends with cell death. However, we do not yet have any idea of how systematic degeneration works, such as degeneration in neurocircuit specific lesions, which remains unsolved even after 100 years of neurodegenerative research. Degenerative research has entered into a period that focuses on the development of treatments. Now we know that removing degenerative proteins in the progressive stage of a disease does not improve symptoms; this has focused our interest on the importance of the early stages of synapse lesions.

On the other hand, with developmental disorders it is becoming clear that there are many common points with the processes of molecular pathology, from cell dysfunction to abnormality of synapses, as well as with degenerative diseases, although the temporal axes are different. Moreover, it is suggested that in mental disease, there is a relation between phenotypes and abnormality in the transmitters and synapses in each part of brain.

In this context, our research aims to clarify the molecular processes by which gene abnormality leads to synapse abnormality by going through various cell dysfunctions, as well as pathology which leads to circuit selectivity in the fields of degenerative disease, developmental disease and mental disease. Besides, we will attempt to make clear the differences and similarities in pathogenesis by comparing achievements gleaned from research into each disease and try to elaborate a new pathological classification as well as a basic strategy of disease treatments. In addition, we will try to visualize a dynamics for a molecular pathology of synapses by using the latest molecular imaging, and promote analysis of synapse pathology in stem cells, including iPS, through their degeneration, recovery and regeneration.

Research we conduct in this area does not concentrate on protein aggregation or on cell death, both of which have been studied so far in brain disease research. This is different from synapse biology, which is based on the analysis of normal synapses. We can establish synapse circuit pathology through analysis from different angles, using next generation high technology, as well as establish the synapse circuit alteration in the lesion itself. Conversely, this could lead to new breakthroughs in our understanding of the normal function of synapses. We believe that the achievements of our research will contribute greatly to the improvement of the study of brain neuronal diseases being carried out in Japan today. The principal investigators of this Scientific Research on Innovative Areas, who have also been responsible for planning the research, have already clarified degeneration by gaining support from Research on Pathomechanisms of Brain Disorders, a theme adopted in the Grant-in-Aid for Scientific Research on Priority Areas project.

We will develop these achievements into a new concept of brain disease, working together with researchers skilled in advanced technology for stem cell research and in molecular imaging.