Open Close
Reference
Citation
Zanon, A., Kalvakuri, S., Rakovic, A., Foco, L., Guida, M., Schwienbacher, C., Serafin, A., Rudolph, F., Trilck, M., Grünewald, A., Stanslowsky, N., Wegner, F., Giorgio, V., Lavdas, A.A., Bodmer, R., Pramstaller, P.P., Klein, C., Hicks, A.A., Pichler, I., Seibler, P. (2017). SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.  Hum. Mol. Genet. 26(13): 2412--2425.
FlyBase ID
FBrf0236503
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC6192413 (PMC) (EuropePMC)
Related Publication(s)
Erratum

Corrigendum: SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.
Zanon et al., 2019, Hum. Mol. Genet. 28(7): 1225 [FBrf0241792]

Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Hum. Mol. Genet.
    Title
    Human Molecular Genetics
    Publication Year
    1992-
    ISBN/ISSN
    0964-6906
    Data From Reference
    Aberrations (2)
    Alleles (9)
    Genes (4)
    Human Disease Models (1)
    Natural transposons (1)
    Experimental Tools (1)
    Transgenic Constructs (8)