6-Hydroxydopamine induces cystatin C-mediated cysteine protease suppression and cathepsin D activation

Daniel C. Lee, Tracy A. Womble, Ceceile W. Mason, Inneke M. Jackson, Nazarius S. Lamango, Walter B. Severs, Donald E. Palm

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Alteration in the lysosomal system (LS) may represent a central mechanism in neurodegeneration. 6-Hydroxydopamine (6-OHDA) induces oxidative stress and cell death in catecholaminergic cells. The LS and caspases participate in apoptosis, although the mechanism(s) that is involved is not completely understood. Here, we show that Pheochromocytoma (PC12) cells exposed to 6-OHDA results in lysosomal dysregulation, caspase activation and cell death. Cells exposed to 6-OHDA increased expression and release of cystatin C (CC) and suppressed cathepsin B (CB). CB activity significantly declined 24 h following exposure to 6-OHDA, however neutralization of CC restored CB activity. Cathepsin D (CD) and caspase-3 activity also increased following exposure to 6-OHDA. Inhibition of CD and caspase-3 with pepstatin A (PA) and DEVD-Cho, respectively, attenuated the 6-OHDA induced cell death at 48 and 72 h. However, the CB inhibitor CA-074Me failed to protect cells. Additionally, poly-ADP-ribose polymerase (PARP) cleavage was evaluated after exposure to 6-OHDA and PA, CA-074Me, and DEVD-Cho. Only DEVD-Cho significantly decreased PARP cleavage following exposure to 6-OHDA. Hence, caspase-3 mediated PARP cleavage following exposure to 6-OHDA appears independent of CB and CD alterations. These studies suggest alternate pathways and potential therapeutic targets of cell death associated with oxidative stress, CC, and lysosomal dysregulation.

Original languageEnglish
Pages (from-to)607-618
Number of pages12
JournalNeurochemistry International
Volume50
Issue number4
DOIs
StatePublished - Mar 2007

Bibliographical note

Funding Information:
We would like to thank Dr. Karam F.A. Soliman, Mrs. Glory Brown, Mrs. Frances James, Mrs. Brenda Arnold, Ms. Shalonda Fagg, and Mrs. Pamela Bryant for editorial assistance. Supported by NIH/NIGMS/MBRS S06 GM 0811, NIH/NCRR/RCMI G12RR03020.

Keywords

  • 6-OHDA
  • Cathepsin
  • Cystatin C
  • Neurodegeneration
  • PC12 cells
  • Parkinson's

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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