Clarification of Mechanisms Underlying Development of Hereditary Parkinsonﾕs Disease Laboratory for Motor System Neurodegeneration Background of study Parkinsonﾕs disease is a neurodegenerative disease, the main symptom of which is progressive motor disturbance. In Japan, the number of patients with the disease is estimated to be approximately one hundred thousand. Neuropathologically, the disease is characterized by selective degeneration of dopamine-producing neurons in the midbrain nigra. Parkinsonﾕs disease is believed to be hereditary in approximately 5% of patients. Autosome recessive hereditary juvenile Parkinsonism (AR-JP) occurs particularly in those who are 40 years or under. The cause of AR-JP is the lack of the gene called Parkin. In 2000, we and other groups clarified that Parkin is an enzyme which promotes decomposition of a particular protein. Based on this finding, we considered that a protein (substrate) that should have been decomposed by Parkin is accumulated in dopamine-producing neurons, resulting in their degeneration. We further considered that clarification of the substrate of Parkin is the key to revealing mechanisms underlying the development of AR-JP. Currently, we, a team involved in the study of motor neurodegeneration in cooperation with Juntendo University, succeeded in identifying the substrate of Parkin, which is believed to play a significant role in the development of AR-JP. Results Using the yeast two-hybrid system, the Parkin-associated endothelin receptor-like (Pael) protein was identified as the membrane protein that binds to Parkin. The following have also been clarified. 1. Decomposition of Pael is promoted by Parkin. 2. Pael is difficult to fold properly. Pael that fails to fold properly is rapidly decomposed by Parkin. 3. In experiments using cultured cells, when decomposition of Pael is inhibited by drugs, unfolded Pael accumulates abnormally in the endoplasmic reticulum (ER). Finally, cell death occurs due to stress on the ER. 4. Pael is not decomposed in the brain of patients with AR-JP and is accumulated in amounts 10 to 30 times greater than that in the brains of patients without AR-JP. 5. Pael is actively expressed in oligodendroglia cells in the brain and in general, less actively in neurons. However, Pael is particularly expressed in exceptionally high amounts in dopamine-producing neurons in the midbrain nigra, which has lesions in AR-JP proteins. Based on these findings, we assume that in AR-JP, due to abnormal accumulation of Pael that fails to fold properly, cell death selectively occurs in some dopamine-producing neurons, resulting in development of AR-JP (refer to Figure). Prospects for the future We expect that based on this study a treatment method that targets Pael and prevents degeneration of dopamine-producing neurons will be developed. In concrete terms, by inhibiting production of Pael or promoting decomposition of Pael, treatment for AR-JP will be realized. In addition, this study showed that abnormal accumulation of proteins, such as Pael, that did not fold properly in neurons may possibly cause neurodegeneration as in sporadic Parkisonﾕs disease. Studying this possibility further may enable us to develop a treatment method for Parkinsonﾕs disease. Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y. and Takahashi, R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell, 105, 891-902, 2001. 　 Mechanisms underlying development of hereditary Parkinsonﾕs disease: when Parkin failure occurs, unfolded Pael accumulates abnormally in the ER, causing ER stress and ultimately cell death.