Associate Professor

Yuzuru IMAI, Ph.D

Improved medical technologies and living environments have provided this longevity society together with an increment of the elderly with neurodegenerative diseases. Age-dependent neurodegenerative diseases contain a cognitive disorder Alzheimer’s disease and a motor disorder Parkinson’s disease. These diseases are caused by progressive degeneration of the specific neuronal populations. However, little is known about the cause of neurodegeneration.
Our aim is to figure out the molecular mechanism of neurodegeneration, especially in Parkinson’s disease, the second common neurodegenerative disease to Alzheimer’s. Small part of Parkinson’s disease is inherited. These responsible genes have been identified, which has allowed a molecular biological approach to this disease (Figure 1). Although mutations of these genes lead to progressive degeneration of the dopaminergic neurons in the substantia nigra of the midbrain, and eventually to Parkinson’s disease, there are open questions that how these gene mutations contribute to the neurodegeneration and that how each gene is involved in a common neurodegenerative pathway. To address these questions, we employ model animals for familial Parkinson’s disease (Figures 2-4). Brain aging is an important risk factor for age-dependent neurodegenerative disorders. We will approach the molecular mechanism of brain aging as well. These results from our study will help elucidation of the pathogenesis of sporadic Parkinson’s and Alzheimer’s diseases, most part of these diseases.

Figure 1. Genes responsible for familial Parkinson’s disease.
The gene products have various protein functions. It is important to clarify whether these genes are involved in a common neuropathological pathway or not. Recently we have reported that there is a genetic interaction between park2 and park6 in Drosophila.

Figure 2. Dopaminergic neurons in the posterior part of the Drosophila adult brain.
Each dopaminergic nucleus consists of 4 − 15 neurons. In the fly models for Parkinson’s disease, neurons in protocerebral posterior lateral 1 (PPL1) and protocerebral posterior medial 2 (PPM2, circles) are markedly affected. It is easy to evaluate the results since Drosophila has much less of dopaminergic neurons and a shorter lifespan when compared with mouse models.

Figure 3. A genetic interaction in the eye.
Overexpression of tau R406W, which causes the typical paired helical filaments (PHF) as seen in Alzheimer’s and Parkinson’s disease patients, in the compound eyes of Drosophila results in a retinal degeneration (middle). Although expression of a Parkinson’s disease-associated gene has no effects on the eye development (left), co-expression of the gene for Parkinson’s disease with the mutant tau enhances the mutant tau-mediated eye degeneration (right). Visible disease phenotypes such as tau R406W fly eyes enable large-scale screenings for genetic interactions or therapeutic agents.

Figure 4. Dopaminergic neurons of the substantia nigra of the midbrain project these axons to the striatum. Clinical symptoms of Parkinson’s disease are mainly due to the lack of dopamine in the striatum. The brain architecture of Drosophila is different from that of human brain while murine brain is basically the same as human. Immunostaining of tyrosine hydroxylase a marker for dopaminergic neurons in a sagittal section of the mouse brain (upper, brown). Nigrostriatal pathway affected in Parkinson’s disease (Lower, magenta).

Major publications（2000-2010）

1. Imai Y*, Kanao T*, Sawada T, Kobayashi Y, Moriwaki Y, Ishida Y, Takeda K, Ichijo H, Lu B, Takahashi R: The Loss of PGAM5 Suppresses the Mitochondrial Degeneration Caused by Inactivation of PINK1 in Drosophila. PLoS Genet. in press. *These authors contributed equally to this paper.
2. Nagao Y, Imai Y, Matsui J, Ogawa T, Miyashita T: Proton transport properties of poly(aspartic acid) with different average molecular weights. J. Chem. Thermodyn. in press.
   
3. Kanao T, Venderova K, Park DS, Unterman T, Lu B, Imai Y: Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum Mol Genet. 19: 3747-3758 (2010)
4. Gehrke S, Imai Y, Sokol N, Lu B: Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466: 637-641 (2010)
5. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B: Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27: 2432-2443 (2008)
6. Wang HQ, Imai Y, Inoue H, Kataoka A, Iita S, Takahashi R: Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. J Neurochem. 107: 171-185 (2008)
7. Wang, JW., Imai, Y., Lu, B.: Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1. J Neurosci. 27: 2457-2467 (2007)
8. Kitao, Y., Imai, Y., Ozawa, K., Kataoka, A., Ikeda, T., Soda, M., Namekawa, K., Kiyama, H., Stern, D.M., Hori, O., Wakamatsu, K., Ito, S., Itohara, S., Takahashi. R., Ogawa, S.: Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of Parkin inactivation. Hum Mol Genet.16: 50-60 (2007)
9. Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J-W., Yang, L., Beal, MF., Vogel, H. and Lu, B.: Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by Drosophila PINK1 is rescued by Parkin. Proc Natl Acad Sci U S A. 103: 10793-10798 (2006)
10. Yang, Y., Gehrke, S., Haque, ME., Imai, Y., Kosek, J., Yang, L., Beal, MF., Nishimura, I., Wakamatsu, K., Ito, S., Takahashi, R. and Lu, B.: Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci U S A. 102: 13670-13675 (2005)
11. Imai, Y. and Takahashi, R.: How do Parkin mutations result in neurodegeneration? Curr Opin Neurobiol. 14: 384-389 (2004)
12. Yang, Y., Nishimura, I., Imai, Y., Takahashi, R. and Lu, B.: Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron. 37: 911-924 (2003)
13. Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K-I. and Takahashi, R.: CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell. 10: 55-67 (2002)
14. Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K. and Takahashi, R.: A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 8: 613-621 (2001)
15. Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y. and Takahashi, R.: An unfolded putative membrane transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 105: 891-902 (2001)
16. Imai, Y, Soda, M. and Takahashi, R.: Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem. 275: 35661-35664 (2000)

page top