Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment
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Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment. / Brañas Casas, Raquel; Zuppardo, Alessandro; Risato, Giovanni; Dinarello, Alberto; Celeghin, Rudy; Fontana, Camilla; Grelloni, Eleonora; Gilea, Alexandru Ionut; Viscomi, Carlo; Rasola, Andrea; Dalla Valle, Luisa; Lodi, Tiziana; Baruffini, Enrico; Facchinello, Nicola; Argenton, Francesco; Tiso, Natascia.
I: Cell Death and Disease, Bind 15, Nr. 4, 281, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment
AU - Brañas Casas, Raquel
AU - Zuppardo, Alessandro
AU - Risato, Giovanni
AU - Dinarello, Alberto
AU - Celeghin, Rudy
AU - Fontana, Camilla
AU - Grelloni, Eleonora
AU - Gilea, Alexandru Ionut
AU - Viscomi, Carlo
AU - Rasola, Andrea
AU - Dalla Valle, Luisa
AU - Lodi, Tiziana
AU - Baruffini, Enrico
AU - Facchinello, Nicola
AU - Argenton, Francesco
AU - Tiso, Natascia
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.
AB - The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.
U2 - 10.1038/s41419-024-06622-9
DO - 10.1038/s41419-024-06622-9
M3 - Journal article
C2 - 38643274
AN - SCOPUS:85190828273
VL - 15
JO - Cell Death & Disease
JF - Cell Death & Disease
SN - 2041-4889
IS - 4
M1 - 281
ER -
ID: 392660953