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Disruption of quality control system of protein/organella and Parkinson's diseases

開催日 2014/9/13
時間 17:10 - 19:10
会場 Room E(301)
Chairperson(s) 今居 譲 / Yuzuru Imai (順天堂大学大学院医学研究科 / Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Japan)
長谷川 隆文 / Takafumi Hasegawa (東北大学大学院医学系研究科 / Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Japan)

Retromer dysfunction as an emerging mechanism of Parkinson's disease

  • S3-E-3-1
  • 長谷川 隆文 / Takafumi Hasegawa:1 
  • 1:東北大学 / Department of Neurology, Tohoku University School of Medicine, Japan 

The pathological hallmark of Parkinson's disease (PD) is loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are composed of α-synuclein (αSYN) fibrils. Recently, mutations in vacuolar protein sorting 35 (VPS35) have been identified as a cause for the rare familial form of PD. VPS35, a key component of the retromer, mediates retrograde transport of cargo proteins from the endosome to the trans-Golgi network. To investigate the functional roles of retromer in the pathogenesis of PD, RNAi-mediated silencing of VPS35 was performed using cellular and in vivo human wt-αSYN-expressing Transgenic fly models. We showed that the silencing of VPS35 in cultured cells caused an increase in the lysosomal turnover of the cation-independent mannose 6-phosphate receptor, thereby affecting the trafficking of CTSD, a lysosome protease involved in αSYN degradation. VPS35 knockdown perturbed the maturation step of cathepsin D in parallel with the accumulation of αSYN in the lysosomes. Co-expression of siRNA resistant-wt VPS35 rescued αSYN degradation in VPS35 siRNA-treated cells. Furthermore, RNAi-mediated knockdown of Drosophila melanogaster VPS35 not only induced the accumulation of detergent-insoluble αSYN species in the brain but also exacerbated both compound eye degeneration and locomotor impairments in the flies expressing the human wild-type αSYN. Together, our results provide evidence that retromer plays a crucial role for αSYN catabolism by modulating the processing of lysosomal protease CTSD and would thereby contribute to the disease pathology linked to PD.

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