Proteolysis mechanism of an anomalous protein that causes Parkinson's disease Laboratory for Motor System Neurodegeneration Laboratory for Neural Architecture The Laboratory for Motor System Neurodegeneration and the Laboratory for Neural Architecture have elucidated the proteolysis mechanism of an anomalous protein that causes Parkinson's disease. A hereditary type of Parkinson's disease, which occurs in young people, is caused when rejected proteins accumulate in dopaminergic neurons. This occurs when an enzyme called Parkin, which is involved in proteolysis, functions abnormally. We identified two proteins, Hsp70 and CHIP, that combine with and assist Parkin. We also discovered that these proteins assist Parkin in the decomposition of unwanted proteins. Background Parkinson's disease is caused by selective neurodegenerative and neuronal death processes of dopaminergic neurons in the midbrain substantia nigra site resulting in motor system disorders. However, much of the mechanism that causes this dopaminergic neurodegeneration is still unknown. This disease mostly affects elderly people, and, in today's aging society, the need to understand the pathogenic mechanism and to develop a cure for this devastating disease, is increasingly important. While Parkinson's disease is generally not inherited, there are genetic causes. The gene Parkin, for example, causes autosomal recessive parkinsonism. Parkin has "ubiquitin ligase" enzyme activity, which is involved in proteolysis, and this activity is not observed in (familial) Parkinson's disease, which is caused by mutations of Parkin. In addition, through collaborative research work with Juntendo University, we have identified membrane proteins that are decomposed by Parkin. These proteins are named Pael receptors, and their normal formation process is extremely difficult. Those proteins that are not properly synthesized are decomposed by Parkin. We also learned that if these Pael receptors accumulate in nerve cells, it leads to neuronal death, and this accumulation of Pael receptor occurs in the brains of Parkinson's disease patients. Research results Based on the assumption that there are molecules that support Parkin's enzyme activity,we identified, biochemically, these proteins from cultured nervous system cells. Then we studied the effects of these proteins on ubiquitin ligase activity. We also studied the effects of accumulated Pael receptors on neuronal death. We learned that: 1. Hsp70 and CHIP are proteins that combine with Parkin 2. CHIP enhances Parkin's enzyme activity and promotes decomposition of improperly synthesized Pael receptors, which form substrates of Parkin 3. Hsp70 does not decompose Pael receptors in a test tube, but helps prevent those Pael receptors that do not form from becoming insoluble and not able to be decomposed by decomposing enzymes. 4. The co-existence of CHIP and Hsp70 enhances the Parkin's decomposition activity of Pael receptors. 5. The co-existence of CHIP and Hsp70 suppresses celldeath caused by malformed Pael receptors (see the figure). Future prospects Accumulated anomalous proteins are also a possible cause of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, polyglutamine disease and prion disease, as well as Parkinson's disease. Now that the roles of Hsp70 (to prevent insolubility of misfolded proteins) and CHIP (to help the proteolysis process of anomalous proteins) are identified, the likelihood that a universal cure for diseases caused by accumulated anomalous proteins may be developed in the near future is higher. Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K-i., 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) The survival rate of "human" nerve-like cells depends on existence of Parkin, Hsp70, and CHIP. When only red fluorescent genes (DsRED), as a marker, were introduced into cultured nerve cells in which misfolded Pael receptors cause cell death, those cells (red in left picture) become round and die. When Parkin, Hsp70, and CHIP genes are introduced with the red fluorescent genes (DsRED) however, those cells (red in right picture) retain their normal shape.