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  1. Artikel ; Online: Plectin plays a role in the migration and volume regulation of astrocytes: a potential biomarker of glioblastoma.

    Žugec, Maja / Furlani, Borut / Castañon, Maria J / Rituper, Boštjan / Fischer, Irmgard / Broggi, Giuseppe / Caltabiano, Rosario / Barbagallo, Giuseppe M V / Di Rosa, Michelino / Tibullo, Daniele / Parenti, Rosalba / Vicario, Nunzio / Simčič, Saša / Pozo Devoto, Victorio Martin / Stokin, Gorazd B / Wiche, Gerhard / Jorgačevski, Jernej / Zorec, Robert / Potokar, Maja

    Journal of biomedical science

    2024  Band 31, Heft 1, Seite(n) 14

    Abstract: Background: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and ... ...

    Abstract Background: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes.
    Methods: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively.
    Results: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines.
    Conclusions: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.
    Mesh-Begriff(e) Animals ; Humans ; Mice ; Aquaporin 4 ; Astrocytes ; Biomarkers ; Glioblastoma ; Plectin ; Protein Isoforms
    Chemische Substanzen Aquaporin 4 ; Biomarkers ; Plectin ; Protein Isoforms ; Plec protein, mouse
    Sprache Englisch
    Erscheinungsdatum 2024-01-23
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 1193378-1
    ISSN 1423-0127 ; 1021-7770
    ISSN (online) 1423-0127
    ISSN 1021-7770
    DOI 10.1186/s12929-024-01002-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson's disease.

    Pozo Devoto, Victorio Martin / Dimopoulos, Nicolas / Alloatti, Matías / Pardi, María Belén / Saez, Trinidad M / Otero, María Gabriela / Cromberg, Lucas Eneas / Marín-Burgin, Antonia / Scassa, Maria Elida / Stokin, Gorazd B / Schinder, Alejandro F / Sevlever, Gustavo / Falzone, Tomás Luis

    Scientific reports

    2017  Band 7, Heft 1, Seite(n) 5042

    Abstract: The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause ... ...

    Abstract The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.
    Mesh-Begriff(e) Axonal Transport ; Homeostasis ; Human Embryonic Stem Cells/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Mutant Proteins/metabolism ; Neurons/pathology ; Organelle Size ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Protein Domains ; alpha-Synuclein/chemistry ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
    Chemische Substanzen Mutant Proteins ; alpha-Synuclein
    Sprache Englisch
    Erscheinungsdatum 2017-07-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-05334-9
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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