演題詳細
Oral
パーキンソン病とその類縁疾患 1
Parkinson's Disease and Related Disorders 1
開催日 | 2014/9/12 |
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時間 | 17:10 - 18:10 |
会場 | Room I(311+312) |
Chairperson(s) | 小澤 健太郎 / Kentaro Ozawa (奈良県立医科大学 / Nara Medical University, Japan) 山門 穂高 / Hodaka Yamakado (京都大学大学院医学研究科 臨床神経学 / Department of Neurology, Kyoto University Graduate School of Medicine, Japan) |
TBK1によるp62のリン酸化を介したマイトファジーの制御機構
TBK1 controls PINK1/Parkin-dependent mitophagy through p62/SQSTM1 phosphorylation
- O2-I-5-1
- 松本 弦 / Gen Matsumoto:1,2 貫名 信行 / Nobuyuki Nukina:1
- 1:順天大院 医 神経変性疾患病態治療探索講座 / Juntendo University, Grad. School. Med., Dept. Neurosci. Neurodegenerative disorders, Japan 2:理研BSI視床発生 / RIKEN, BSI, Japan
Various neurodegenerative diseases including Parkinson's diseases (PD) correlate with mitochondrial dysfunction. Mutations in Parkin (PARK2) or PINK1 (PARK6) gene cause autosomal recessive familial PD and those gene products have a critical role in the autophagic elimination of depolarized mitochondria, called PINK1/Parkin-dependent mitophagy. Although PINK1 and Parkin play a key role in the mitochondria surveillance by marking depolarized mitochondria with polyubiquitin chain, it is unclear how the ubiquitin-coated mitochondria are engulfed by autophagosomes. We showed here that p62/SQSTM1, a key autophagic adaptor protein, was immediately recruited to ubiquitinated mitochondria and phosphorylated at S403 upon the CCCP, a mitochondrial uncoupler, treatment. p62 phosphorylation was indued by CCCP treatment, but was attenuated in accordance with mitochondrial cluster formation. In the early time periods of PINK1/Parkin-dependent mitophagy, a limited amount of mitochondria recruited Parkin and p62. Optineurin, the other autophagic adaptor protein, was partially recruited to Parkin-recruited mitochondria with TANK-binding kinase 1 (TBK1). TBK1 was activated at the mitochondria and directly phosphorylated p62 at S403. Without Optineurin-mediated TBK1 activation at Parkin-recruited mitochondria, p62 phosphorylation was interrupted, resulting in prevention of autophagosomal engulfment of depolarized mitochondria and acceleration of mitochondrial cluster formation. Our results suggest that the involvement of Optineurin-TBK1-p62 proteins in both mitopahgy and xenophagy may represent a general regulation system for selective autophagic engulfment of various autophagic cargos. In this regard, the accumulation of ubiquitin and p62 positive inclusions including Lewy bodies may reflect the isolated autophagic cargoes caused by dysfunction of Optineurin-TBK1-p62-mediated selective autophagy.