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Hum Mol Genet. 2017 Jul 1;26(13):2412-2425. doi: 10.1093/hmg/ddx132.

SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.

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Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
Molecular and Functional Neurobiology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
University of Padova, 35122 Padova, Italy.
Department of Neurology, General Central Hospital, 39100 Bolzano, Italy.
Department of Neurology, University of Lübeck, 23562 Lübeck, Germany.


Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. SH-SY5Y cells with a stable knockdown of Parkin or SLP-2, as well as induced pluripotent stem cell-derived neurons from Parkin mutation carriers, showed decreased complex I activity and altered mitochondrial network morphology. Importantly, induced expression of SLP-2 corrected for these mitochondrial alterations caused by reduced Parkin function in these cells. In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes, in particular loss of dopaminergic neurons, mitochondrial network structure, reduced ATP production, and flight and motor dysfunction. The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies.

[Indexed for MEDLINE]

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