In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts

Kamienieva, I; Charzyńska, Agata; Duszyński, Jerzy; Malińska, Dominika; Szczepanowska, Joanna

doi:10.1016/j.bbadis.2023.166787

Cited by 2 publications

(1 citation statement)

References 117 publications

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“…Furthermore, PRKN -patient neurons revealed deficits in mitochondrial biogenesis linked to metabolic modulation of the Sirtuin1/PGC1-α pathway and resulting in mtDNA dyshomeostasis and neuroinflammation [ 27 ]. Suppression or knockout of PRKN in Drosophila , zebrafish, mice and human patient cells leads to decreased ATP production, complex I activity, an altered mitochondrial morphology, locomotor impairments, and neuronal loss [ 28 – 32 ]. Parkin is also implicated in mitochondrial dynamics, increased lifespan, reduced proteotoxicity, and sequestration of reactive dopamine metabolites [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2

Zanon,

Guida,

Lavdas

et al. 2024

J Transl Med

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Background Loss-of-function mutations in the PRKN gene, encoding Parkin, are the most common cause of autosomal recessive Parkinson’s disease (PD). We have previously identified mitoch ondrial Stomatin-like protein 2 (SLP-2), which functions in the assembly of respiratory chain proteins, as a Parkin-binding protein. Selective knockdown of either Parkin or SLP-2 led to reduced mitochondrial and neuronal function in neuronal cells and Drosophila, where a double knockdown led to a further worsening of Parkin-deficiency phenotypes. Here, we investigated the minimal Parkin region involved in the Parkin-SLP-2 interaction and explored the ability of Parkin-fragments and peptides from this minimal region to restore mitochondrial function. Methods In fibroblasts, human induced pluripotent stem cell (hiPSC)-derived neurons, and neuroblastoma cells the interaction between Parkin and SLP-2 was investigated, and the Parkin domain responsible for the binding to SLP-2 was mapped. High resolution respirometry, immunofluorescence analysis and live imaging were used to analyze mitochondrial function. Results Using a proximity ligation assay, we quantitatively assessed the Parkin-SLP-2 interaction in skin fibroblasts and hiPSC-derived neurons. When PD-associated PRKN mutations were present, we detected a significantly reduced interaction between the two proteins. We found a preferential binding of SLP-2 to the N-terminal part of Parkin, with a highest affinity for the RING0 domain. Computational modeling based on the crystal structure of Parkin protein predicted several potential binding sites for SLP-2 within the Parkin RING0 domain. Amongst these, three binding sites were observed to overlap with natural PD-causing missense mutations, which we demonstrated interfere substantially with the binding of Parkin to SLP-2. Finally, delivery of the isolated Parkin RING0 domain and a Parkin mini-peptide, conjugated to cell-permeant and mitochondrial transporters, rescued compromised mitochondrial function in Parkin-deficient neuroblastoma cells and hiPSC-derived neurons with endogenous, disease causing PRKN mutations. Conclusions These findings place further emphasis on the importance of the protein–protein interaction between Parkin and SLP-2 for the maintenance of optimal mitochondrial function. The possibility of restoring an abolished binding to SLP-2 by delivering the Parkin RING0 domain or the Parkin mini-peptide involved in this specific protein–protein interaction into cells might represent a novel organelle-specific therapeutic approach for correcting mitochondrial dysfunction in Parkin-linked PD.

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Section: Introductionmentioning

confidence: 99%

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2

Zanon,

Guida,

Lavdas

et al. 2024

J Transl Med

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Significance of Mitochondrial Dysfunction in the Pathogenesis of Parkinson's Disease

Blagov,

Postnov,

Sukhorukov

et al. 2024

Front. Biosci. (Landmark Ed)

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Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic neurons of the corpus striatum, which can be caused by the disruption of processes of mitochondrial homeostasis, including mitophagy, mitochondrial fusion and division, mitochondrial transport, accumulation of reactive oxygen species (ROS), and calcium signaling. Dopaminergic neurons are particularly vulnerable to mitochondrial dysfunction due to their polarized and expanded structure and high bioenergy needs. The molecular basis of these disorders is manifested in mutations of mitochondrial homeostasis proteins. Understanding the functions of these proteins and the disorders caused by these mutations can be used to create therapeutics for the treatment of PD and diagnostic biomarkers of PD. A comprehensive analysis of research papers to identify promising therapeutic targets and drug compounds that target them, as well as biomarkers of mitochondrial dysfunction that can be used in clinical practice for the treatment of PD has been conducted in the current review. This practical approach advantageously emphasizes the difference between this work and other reviews on similar topics. The selection of articles in this review was carried out using the following keyword searches in scientific databases: PubMed, Google Scholar, NSBI, and Cochrane. Next, the most relevant and promising studies were re-selected.

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In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts

Cited by 2 publications

References 117 publications

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2

Significance of Mitochondrial Dysfunction in the Pathogenesis of Parkinson's Disease

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