2022年6月30日 16:10～16:40 沖縄コンベンションセンター 劇場棟 第1会場
1AL-01e-01
パーキンソン病を抑制するマイトファジー
Mitophagy dysfunction relevant to the hereditary Parkinson's disease
*松田 憲之(1)
1. 東京医科歯科大学
*Noriyuki Matsuda(1)
1. Tokyo Medical and Dental University
Keyword: ubiquitin-mediated mitophagy, PINK1, Parkin, Parkinson's disease
Parkinson's disease (PD) is a common movement disorder characterized by dopaminergic neuronal loss. The majority of PD cases are sporadic, however, the discovery of the genes linked to hereditary forms of PD (i.e. hereditary Parkinsonism) has provided important insights into the pathogenic mechanisms. Indeed, functional analysis of the recessive familial PD-related genes has revealed that the disease is relevant to mitochondrial quality control. This is consistent with the prior idea that several cases of sporadic PDs and chemical-induced Parkinsonism have been associated with mitochondrial dysfunction.
We have focused on PINK1 and PARKIN, responsible genes for hereditary recessive PD. PINK1 and PARKIN encode Ser/Thr kinase and ubiquitin ligase (E3), respectively. We revealed that when the mitochondrial membrane potential decreased in cultured cells, PINK1 and Parkin cooperate to put ubiquitin chains on the damaged mitochondria. Parkin-catalyzed ubiquitin chain functions as a degradation signal via selective autophagy (mitophagy). However, the molecular mechanisms are not well understood how the ubiquitin chain is selectively conjugated on the damaged mitochondria and how it is decoded as a degradation signal.
We have revealed that PINK1 phosphorylates ubiquitin at Ser65, and the phosphorylated ubiquitin functions as an activator for Parkin (Koyano, Nature 2014). Moreover, phosphorylated ubiquitin chain recruits Parkin to damaged mitochondria by functioning as a Parkin receptor (Okatsu, JCB 2015). Consequently, trio of PINK1, Parkin, and phospho-ubiquitin rapidly and heavily tag outer membrane proteins on depolarized mitochondria with ubiquitin. We revealed that the ubiquitin chain is recognized by RABGEF1, and it directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria for degradation by lysosome (Yamano, eLife 2018). Moreover, ubiquitin chains on depolarized mitochondria are also recognized by autophagy adaptor OPTN, which subsequently interacts with ATG9 (an important autophagy-related factor that provides membrane during autophagosome formation) to induce local mitophagy (Yamano, JCB 2020). Recently we identified novel factors BCAS3 and C16orf70 that associate with the autophagosome formation site during Parkin-mediated mitophagy. BCAS3 and C16orf70 form a complex, and a regulatory role of this complex during autophagy is suggested (Kojima, Autophagy 2021).
In this presentation, we will discuss the molecular mechanisms how ubiquitin chains added to damaged mitochondria by PINK1 and Parkin induce mitophagy, which might suppress the onset of Parkinson’s disease. | | 2022年6月30日 16:40～17:10 沖縄コンベンションセンター 劇場棟 第1会場
1AL-01e-02
霊長類脳回路の可視化と操作による機能理解
Visualizing and manipulating primate brain circuits and functions
*南本 敬史(1)
1. 量子科学技術研究開発機構
*Takafumi Minamimoto(1)
1. Natl Inst Quant Sci&Tech, Chiba, Japan
Keyword: monkey, DREADDs, PET, decision-making
Non-human primates, especially macaque and marmoset monkeys are excellent models for elucidating highly organized brain function and behavior. However, the application of optogenetics or chemogenetics to monkeys is still limited, preventing a network-level understanding of the higher brain functions. We have been working on the application of a chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to non-human primates. DREADDs afford a means of reversibly and remotely controlling the activity of a neuronal population expressing designer receptors through delivery of their agonist. We have identified a highly potent and selective DREADD agonist, deschloroclozapine (DCZ), which can also be used as a PET imaging probe to monitor the expression of DREADD designer receptors in living monkeys. Combined with PET and MR imaging, DREADDs are now a powerful and attractive tool for non-human primate research to visualize and manipulate specific brain circuits and monitor induced network activity changes. This talk will summarize the current status and prospects of chemogenetic technology that links primate brain circuits and behavior and opens up possibilities for developing therapeutic applications. |
