Translocation of Lysosomal Cathepsin D Caused by Oxidative Stress or Proteasome Inhibition in Primary Cultured Neurons and Astrocytes

Miura Yuri, Sakurai Yoko, Hayakawa Masato, Shimada Yukiko, Zempel Hans, Sato Yuji, Hisanaga Shin-ichi, Endo Tamao

doi:10.1248/bpb.33.22

We reported previously that N-linked glycoproteins were accumulated in the cytosol of the normal aging rat brain, and that one protein had been identified as cathepsin D (Mech. Ageing Dev., 127, 771—778 (2006)). In this study, to elucidate the mechanism of cathepsin D accumulation in the cytosol, we examined the effects of oxidative stress and proteasome inhibition on the apoptosis and subcellular localization of cathepsin D in primary cultured neurons and astrocytes. Using 4′-6-diamidino-2-phenylindole (DAPI)- or Hoechst 33342-staining and annexin V detection, we found that oxidative stress caused by tert-butyl hydroperoxide and proteasome inhibition by lactacystin induced apoptosis in neurons and astrocytes. Furthermore, after cell fractionation, it was demonstrated that cathepsin D was translocated from lysosomes to cytosol under apoptosis-inducing conditions in both cells. These results suggested that oxidative stress and the suppression of proteasome activity triggered the translocation of cathepsin D from lysosomes to cytosol. The possible mechanism of age-related accumulation of cathepsin D in the cytosol of the normal rat brain will be discussed.

Translocation of Lysosomal Cathepsin D Caused by Oxidative Stress or Proteasome Inhibition in Primary Cultured Neurons and Astrocytes

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