Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress

Miratul M. K. Muqit, Patrick M. Abou-Sleiman, Adrian T. Saurin, Kirsten Harvey, Sonia Gandhi, Emma Deas, Simon Eaton, Martin D. Payne Smith, Kerrie Venner, Antoni Matilla, Daniel G. Healy, William P. Gilks, Andrew J. Lees, Janice Holton, Tamas Revesz, Peter J. Parker, Robert J. Harvey, Nicholas W. Wood, David S. Latchman

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Abstract

Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.

Original languageEnglish
Pages (from-to)156-169
Number of pages14
JournalJournal of Neurochemistry
Volume98
Issue number1
Early online date30 May 2006
DOIs
Publication statusPublished - Jul 2006

Keywords

  • Autosomal-recessive juvenile parkinsonism
  • Lewy body
  • Microtubule organizing centre
  • Mitochondrial processing peptidase
  • Parkinson's disease
  • Ubiquitin-proteasome system

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    Muqit, M. M. K., Abou-Sleiman, P. M., Saurin, A. T., Harvey, K., Gandhi, S., Deas, E., Eaton, S., Payne Smith, M. D., Venner, K., Matilla, A., Healy, D. G., Gilks, W. P., Lees, A. J., Holton, J., Revesz, T., Parker, P. J., Harvey, R. J., Wood, N. W., & Latchman, D. S. (2006). Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. Journal of Neurochemistry, 98(1), 156-169. https://doi.org/10.1111/j.1471-4159.2006.03845.x