Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2 Article Swipe
Alessandra Zanon
,
Marianna Guida
,
Alexandros Α. Lavdas
,
Corrado Corti
,
Maria Paulina Castelo Rueda
,
Alessandro Negro
,
Peter P. Pramstaller
,
Francisco S. Domingues
,
Andrew A. Hicks
,
Irene Pichler
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1186/s12967-024-04850-3
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1186/s12967-024-04850-3
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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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1186/s12967-024-04850-3
- https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-04850-3
- OA Status
- gold
- Cited By
- 2
- References
- 100
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4390904349
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4390904349Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1186/s12967-024-04850-3Digital Object Identifier
- Title
-
Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2Work title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-01-16Full publication date if available
- Authors
-
Alessandra Zanon, Marianna Guida, Alexandros Α. Lavdas, Corrado Corti, Maria Paulina Castelo Rueda, Alessandro Negro, Peter P. Pramstaller, Francisco S. Domingues, Andrew A. Hicks, Irene PichlerList of authors in order
- Landing page
-
https://doi.org/10.1186/s12967-024-04850-3Publisher landing page
- PDF URL
-
https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-04850-3Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-04850-3Direct OA link when available
- Concepts
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Parkin, Gene knockdown, Cell biology, Mitochondrion, Biology, HEK 293 cells, Phenotype, Proximity ligation assay, Molecular biology, Genetics, Parkinson's disease, Cell culture, Gene, Receptor, Medicine, Disease, PathologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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2Total citation count in OpenAlex
- Citations by year (recent)
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2024: 2Per-year citation counts (last 5 years)
- References (count)
-
100Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| primary_location.pdf_url | https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-04850-3 |
| primary_location.version | publishedVersion |
| primary_location.raw_type | journal-article |
| primary_location.license_id | https://openalex.org/licenses/cc-by |
| primary_location.is_accepted | True |
| primary_location.is_published | True |
| primary_location.raw_source_name | Journal of Translational Medicine |
| primary_location.landing_page_url | https://doi.org/10.1186/s12967-024-04850-3 |
| publication_date | 2024-01-16 |
| publication_year | 2024 |
| referenced_works | https://openalex.org/W4211123396, https://openalex.org/W2097777783, https://openalex.org/W2972937106, https://openalex.org/W4285018488, https://openalex.org/W2796389302, https://openalex.org/W3049557897, https://openalex.org/W3114319447, https://openalex.org/W4388590203, https://openalex.org/W4294970551, https://openalex.org/W3029936992, https://openalex.org/W2060542273, https://openalex.org/W3011802680, https://openalex.org/W2797194936, https://openalex.org/W2985058906, https://openalex.org/W1894946963, https://openalex.org/W2095348121, https://openalex.org/W1550876205, https://openalex.org/W2038976751, https://openalex.org/W4365149043, https://openalex.org/W2102136953, https://openalex.org/W2082425146, https://openalex.org/W2155015733, https://openalex.org/W2106444069, https://openalex.org/W3088148337, https://openalex.org/W3048517366, https://openalex.org/W1993098682, https://openalex.org/W2160697936, https://openalex.org/W4224309273, https://openalex.org/W2055124287, https://openalex.org/W2165783038, https://openalex.org/W2140647923, https://openalex.org/W2995887029, https://openalex.org/W4380091326, https://openalex.org/W2074111563, https://openalex.org/W3133502202, https://openalex.org/W2039586060, https://openalex.org/W2604531607, https://openalex.org/W2130106722, https://openalex.org/W2166886529, https://openalex.org/W1650009710, https://openalex.org/W2529901935, https://openalex.org/W2067712920, https://openalex.org/W1823096434, https://openalex.org/W2556148213, https://openalex.org/W4212959738, https://openalex.org/W1911261579, https://openalex.org/W4286854075, https://openalex.org/W2982170500, https://openalex.org/W2130128490, https://openalex.org/W3188493034, https://openalex.org/W4366290764, https://openalex.org/W4206062431, https://openalex.org/W2158328957, https://openalex.org/W2034414337, https://openalex.org/W1602088950, https://openalex.org/W2069330317, https://openalex.org/W2004908477, https://openalex.org/W2097062199, https://openalex.org/W2093650005, https://openalex.org/W2069403245, https://openalex.org/W1985222378, https://openalex.org/W2043699100, https://openalex.org/W2141627824, https://openalex.org/W2072284383, https://openalex.org/W1985109370, https://openalex.org/W2117335809, https://openalex.org/W2024794315, https://openalex.org/W2069139079, https://openalex.org/W2166263915, https://openalex.org/W2122703782, https://openalex.org/W1986248905, https://openalex.org/W2759702183, https://openalex.org/W2052790020, https://openalex.org/W1969877067, https://openalex.org/W2121077787, https://openalex.org/W2037064466, https://openalex.org/W4309047401, https://openalex.org/W2157300795, https://openalex.org/W2783018670, https://openalex.org/W4386441590, https://openalex.org/W2026540198, https://openalex.org/W3022670067, https://openalex.org/W1969472852, https://openalex.org/W1985359736, https://openalex.org/W1963556899, https://openalex.org/W2002410880, https://openalex.org/W1992450378, https://openalex.org/W1978859117, https://openalex.org/W2946033191, https://openalex.org/W2012987104, https://openalex.org/W2912930263, https://openalex.org/W2903090167, https://openalex.org/W4205604870, https://openalex.org/W2010490262, https://openalex.org/W2989876193, https://openalex.org/W1722845210, https://openalex.org/W2031535129, https://openalex.org/W4379114314, https://openalex.org/W2029919426, https://openalex.org/W632562745 |
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