title: SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.
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.
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zanon
authors.affiliation: Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Sreehari
authors.initials: S
authors.lastname: Kalvakuri
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Foco
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Guida
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Christine
authors.initials: C
authors.lastname: Schwienbacher
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Serafin
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rudolph
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Trilck
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.affiliation: Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Stanslowsky
authors.affiliation: Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.affiliation: University of Padova, 35122 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Alexandros A
authors.initials: AA
authors.lastname: Lavdas
authors.affiliation: Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.|Department of Neurology, General Central Hospital, 39100 Bolzano, Italy.|Department of Neurology, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.affiliation: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Pichler
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
mesh_terms: D000368:Aged; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C406287:STOML2 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D042967:Electron Transport Complex I