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

Research output: Contribution to journalArticle

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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

Fingerprint

Parkinson Disease
Lewy Bodies
Mitochondria
Mitochondrial Proteins
Brain
Proteasome Endopeptidase Complex
Fractionation
PTEN-induced putative kinase
Proteins
Genes
Mutation
Antibodies

Keywords

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

Cite this

Muqit, Miratul M. K. ; Abou-Sleiman, Patrick M. ; Saurin, Adrian T. ; Harvey, Kirsten ; Gandhi, Sonia ; Deas, Emma ; Eaton, Simon ; Payne Smith, Martin D. ; Venner, Kerrie ; Matilla, Antoni ; Healy, Daniel G. ; Gilks, William P. ; Lees, Andrew J. ; Holton, Janice ; Revesz, Tamas ; Parker, Peter J. ; Harvey, Robert J. ; Wood, Nicholas W. ; Latchman, David S. / Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. In: Journal of Neurochemistry. 2006 ; Vol. 98, No. 1. pp. 156-169.
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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.",
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Muqit, MMK, Abou-Sleiman, PM, Saurin, AT, Harvey, K, Gandhi, S, Deas, E, Eaton, S, Payne Smith, MD, Venner, K, Matilla, A, Healy, DG, Gilks, WP, Lees, AJ, Holton, J, Revesz, T, Parker, PJ, Harvey, RJ, Wood, NW & Latchman, DS 2006, 'Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress', Journal of Neurochemistry, vol. 98, no. 1, pp. 156-169. https://doi.org/10.1111/j.1471-4159.2006.03845.x

Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. / Muqit, Miratul M. K.; Abou-Sleiman, Patrick M.; Saurin, Adrian T.; Harvey, Kirsten; Gandhi, Sonia; Deas, Emma; Eaton, Simon; Payne Smith, Martin D.; Venner, Kerrie; Matilla, Antoni; Healy, Daniel G.; Gilks, William P.; Lees, Andrew J.; Holton, Janice; Revesz, Tamas; Parker, Peter J.; Harvey, Robert J.; Wood, Nicholas W.; Latchman, David S.

In: Journal of Neurochemistry, Vol. 98, No. 1, 07.2006, p. 156-169.

Research output: Contribution to journalArticle

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T1 - Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress

AU - Muqit, Miratul M. K.

AU - Abou-Sleiman, Patrick M.

AU - Saurin, Adrian T.

AU - Harvey, Kirsten

AU - Gandhi, Sonia

AU - Deas, Emma

AU - Eaton, Simon

AU - Payne Smith, Martin D.

AU - Venner, Kerrie

AU - Matilla, Antoni

AU - Healy, Daniel G.

AU - Gilks, William P.

AU - Lees, Andrew J.

AU - Holton, Janice

AU - Revesz, Tamas

AU - Parker, Peter J.

AU - Harvey, Robert J.

AU - Wood, Nicholas W.

AU - Latchman, David S.

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AB - 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.

KW - Autosomal-recessive juvenile parkinsonism

KW - Lewy body

KW - Microtubule organizing centre

KW - Mitochondrial processing peptidase

KW - Parkinson's disease

KW - Ubiquitin-proteasome system

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