Analysis of the molecular mechanism of the neuropsychiatric disorders



Analysis of the molecular mechanism of the intellectual disability (ID)
 In this study, we focused on a protein, Cereblon (CRBN), which is encoded by a candidate gene for autosomal recessive nonsyndromic ID. We showed in the presence of a proteasome inhibitor, CRBN works as a component of E3 ubiquitin ligase complex, and be recruited to aggresome to suppress cell death. On the hypothesis that CRBN is a multifunctional protein, we are analyzing the functions of CRBN to explore ID pathogenesis mechanism.

Analysis of the molecular mechanism of the Alzheimer’s disease (AD)
 In this study, we focused on nicotinic acetylcholine receptor subunit (CHRNA7). This protein has been thought to play a central role in the pathogenesis of AD and schizophrenia, because it is a candidate gene for schizophrenia and also binds with amyloid ß protein (Aß), a main component protein of senile plaque of AD. We found that arctic Aß bound to CHRNA7 with high affinity and aggregated on it, leading to the inhibition of CHRNA7 functions. In the present study, we are analyzing the detailed mechanism of memory deficit and neuronal death. And we are also searching new substances which can slow down the development of the disease.


Interdisciplinary Research in Bio-Solid State Science, Chiral Science, and Neuropharmacology



Construction of photo-activated energy production in mammalian cells.
 In the collaborative research with Kiyotaka Hara from Kobe University, we have successfully established the mammalian cells that can generate light-driven proton motive force, by mitochondrially expressing the bacterial proton pump proteins, called delta rhodopsin. It is presumed that this system has the potential to be a tool for understanding the molecular mechanisms underlying Parkinson’s diseases, one of the most common progressive neurodegenerative disorders.

Development of the biosensor for detecting a specific biomolecule in Alzheimer’s disease.
 In the collaborative research with Osaka laboratory from Waseda University, we have developed, as an alternative to conventional spectroscopic assays, a simple method for discriminating fibrous amyloid proteins by using a label-free semiconductor-based biosensor. This assay will be a promising protocol for ever-improving amyloid related research, and early diagnosis of Alzheimer’s disease.

Study of the novel effect of thalidomide on neuronal cells.
 We are aiming to explore enantiospecific pharmacological effects of thalidomide, which has a chiral center that allows for two enantiomers, in neuronal cells. Although thalidomide had been withdrawn due to its teratogenicity for a long time, there has been recently increased clinical interests because it has been approved for the drugs of the treatment of multiple myeloma, Hansen’s disease, Crohn’s disease and several cancers. Moreover, a new protein target of thalidomide, cereblon, has been characterized. Our research aim is to explore new enantiospecific pharmacological effects of thalidomide in neuronal cells.


References

[1] Naoya Sawamura, Satoru Wakabayashi, Kodai Matsumoto, Haruka Yamada, Toru Asahi. Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction. Biochemical and biophysical research communications 464, 1054-1059 (2015)
[2] Ye Ju, Toru Asahi, Naoya Sawamura. Arctic mutant Aβ40 aggregates on α7 nicotinic acetylcholine receptors and inhibits their functions. Journal of neurochemistry 131, 667-674 (2014)
[3] Kiyotaka Y. Hara, Takeyoshi Wada, Kuniki Kino, Toru Asahi, Naoya Sawamura. Construction of photoenergetic mitochondria in cultured mammalian cells. Scientific reports 3, 1635 (2013)
[4] Sho Hideshima, Masumi Kobayashi, Takeyoshi Wada, Shigeki Kuroiwa, Takuya Nakanishi, Naoya Sawamura, Toru Asahi, Tetsuya Osaka. A label-free electrical assay of fibrous amyloid β based on semiconductor biosensing. Chemical Communications 50, 3476-3479 (2014)