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Novel insights into the pathogenesis of Parkinson's disease

26.01.2010
In a study carried out within the context of the National Genome Research Network(NGFN) scientists from the Hertie-Institute for Clinical Brain Research (HIH) at the University Hospital of Tübingen, Germany, were able to show, for the first time, that the two proteins associated with Parkinson's disease (PD), PINK1 and Parkin, together control the selective removal of damaged mitochondria from cells. The study also explains how this is achieved. The scientists from Tübingen assume that a disruption of the identified mitochondrial clearance mechanism may result in the pathogenesis of PD. (Advance online publication in Nature Cell Biology 24 January 2010)

Mitochondria, the cellular power plants, are important organelles that support the cells with chemical energy required for many cellular functions. Damaged mitochondria, however, do not produce energy anymore, but rather result in a tremendous increase of harmful oxidative stress that eventually can lead to cell death.

The selective disposal of damaged mitochondria allows a cleanup of the cell and thereby protects from the devastating consequences of mitochondrial dysfunction. In the present study, the team of Dr. Wolfdieter Springer and Prof. Dr. Philipp Kahle for the first time shows how this disposal mechanism works: Both PD-associated proteins, PINK1 and Parkin, cooperate together in order to mark damaged mitochondria for degradation via attachment of the small protein ubiquitin to a channel protein of the mitochondrial outer membrane.

This ubiquitin label serves as a signal for the cell to remove the damaged mitochondria by a "self-eating" process called autophagy (mitochondrial autophagy or mitophagy). Absence of either functional PINK1 or Parkin protein results in a disruption of this important pathway. Thus, perturbations of this disposal mechanism may play a crucial role in the pathogenesis of PD. "The insights gained herein may now provide the basis for the development of therapeutic strategies that prevent PD and other related neurodegenerative diseases by targeting dysfunctional mitochondria for selective autophagy", says Dr. Wolfdieter Springer, leader of the present study.

The scientists now show that PD-associated mutations abrogate the apparently sequential process of mitophagy at distinct steps. The enzymatic function of the mitochondrially localized kinase PINK1 is thereby essential and promotes a fast recruitment of Parkin from its uniform distribution in the cytoplasm to damaged mitochondria. The ubiquitin ligase Parkin, in turn, is required for the attachment of ubiquitin to VDAC1. The identified ubiquitin-label of VDAC1 is then detected by the ubiquitin/autophagic adaptor protein p62/SQSTM1 that targets the damaged organelle as a whole to the autophagic machinery. Interestingly, VDAC1 forms a channel through the outer mitochondrial membrane and has already been suspected to contribute to cell death resulting from mitochondrial damage.

Mitochondrial disturbances as well as disruption of protein degradation pathways have both been associated with the pathogenesis of PD, and PINK1 and Parkin play important roles in these processes. The elucidation of the mitochondrial degradation pathway mediated by PINK1 and Parkin in the present study now provides a functional link between both cellular dysfunctions implicated in the pathogenesis of PD and other neurodegenerative diseases.

Titel of the original publication:
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Authors: Sven Geisler, Kira M. Holmström, Diana Skujat, Fabienne C. Fiesel, Oliver C. Rothfuss, Philipp J. Kahle und Wolfdieter Springer

Nature Cell Biology advance online publication 24 January 2010, http://dx.doi.org/10.1038/ncb2012

Contact:
University of Tübingen, Germany
Hertie-Institute for Clinical Brain Research (HIH)
Cooperation partner German Centre for Neurodegenerative Diseases (DZNE)
Dr. Wolfdieter Springer
Phone: +49 (0) 7071 29 82038
Email: wolfdieter.springer@klinikum.uni-tuebingen.de
and
Prof. Dr. Philipp Kahle
Phone: +49 (0)7071 29 81970
Email: philipp.kahle@uni-tuebingen.de
http://www.hih-tuebingen.de
Hertie-Institute for Clinical Brain Research (HIH)
Press Officer
Kirstin Ahrens
Phone.: +49 (0)7073-500 724, Mobile: 0173/300 53 96
Email : mail@kirstin-ahrens.de
University Hospital Tübingen
Press Officer
Dr. Ellen Katz
Phone: +49 (0)7071-2980112
Email: ellen.katz@med.uni-tuebingen.de

Kirstin Ahrens | idw
Further information:
http://www.hih-tuebingen.de
http://dx.doi.org/10.1038/ncb2012

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