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Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases

Osellame, LD; Duchen, MR; (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy , 9 (10) pp. 1633-1635. 10.4161/auto.25878. Green open access

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Abstract

Mutations in the GBA gene encoding glucocerebrosidase cause Gaucher disease (GD), the most prevalent of the lysosomal storage disorders (LSDs) and increase susceptibility to Parkinson disease (PD). Clinically the two disorders can present in a similar manner with analogous pathological features, suggesting mechanistic links between the two disease states. An increasing body of evidence implicates defects in quality control pathways in both, and suggests that LSDs, as a group, can be classed as disorders of autophagy. Using a mouse model of type II neuronopathic GD, we observed global defects in cellular quality control pathways in midbrain neurons and astrocytes. Our data suggest that downregulation of autophagy, mitophagy and the ubiquitin-proteasome system (UPS) results in accumulation of dysfunctional and fragmented mitochondria, insoluble SNCA/α-synuclein deposits and ubiquitinated proteins. These observations show that dysfunction of cellular quality control pathways lead to impaired energy and free radical homeostasis, providing new insights into the mechanisms of neurodegeneration in GD and illuminating the links between GD and PD.

Type: Article
Title: Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases
Open access status: An open access version is available from UCL Discovery
DOI: 10.4161/auto.25878
Publisher version: http://dx.doi.org/10.4161/auto.25878
Language: English
Additional information: © 2013 Landes Bioscience. This agreement is for authors who agree to publish their work as open access under the Creative Commons Attribution-NonCommercial 3.0 Unported Liscense (http://creativecommons.org/licenses/by-nc/3.0/). This license permits non-commercial unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Gaucher disease, Parkinson disease, UPS, Autophagy, Mitochondria, Mitophagy, Neurodegeneration, α-synuclein
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1404771
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