The role of LRRK on autophagy and its therapeutic aplication to Parkinsonism

• Project/Area Number: 15H04705
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Toyofuku Toshihiko 大阪大学, 医学系研究科, 特任教授(常勤) (60322179)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: パーキンソン病 / ミトコンドリア / LRRK2 / 神経科学 / シグナル伝達 / 再生医学 / オートファジー / LRRK1 / Rab7

Outline of Final Research Achievements

Parkinson disease is genetically caused by mutations in LRRK2. We found that neurons expressing mutant LRRK2 decreased the mitochondrial energetics and mitochondrial calcium signaling. Mitochondrial calcium is introduced through the contact site between endoplasm (ER) and mitochondria and regulates mitochondrial energetics. LRRK2 interacted with mitochondrial ubiquitin ligases, which regulated components in the ER-mitochondrial interaction Neuron expressing mutant LRRK2 inhibited the activities of these ligases, and then accumulated components disturbed the ER-mitochondrial interaction and ER stress response, resulting in the increased ER stress and apoptotic death of neurons. The treatment with activators for PERK, one of the ER stress inducers, rescued these defects in neuron expressing mutant LRRK2. Thus, our result provides new insight for the treatment for Parkinson disease.

Research Products

• [Journal Article] LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. (2016)
  • Author(s): Morimoto K, Baba Y, Shinohara H, Kang S, Nojima S, Kimura T, Ito D, Yoshida Y, Maeda Y, Sarashina-Kida H, Nishide M, Hosokawa T, Kato Y, Hayama Y, Kinehara Y, Okuno T, Takamatsu H, Hirano T, Shima Y, Narazaki M, Kurosaki T, Toyofuku T, Kumanogoh A.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 25738-25738
  • DOI: 10.1038/srep25738
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation (2015)
  • Author(s): Toyofuku T, Morimoto K, Sasawatari S, Kumanogoh A
  • Journal Title: Mol Cell Biol. Volume: 35(17) Issue: 17 Pages: 3044-58
  • DOI: 10.1128/mcb.00085-15
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant