PUBLICATION

PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons

Authors
Brown, S.J., Boussaad, I., Jarazo, J., Fitzgerald, J.C., Antony, P., Keatinge, M., Blechman, J., Schwamborn, J.C., Krüger, R., Placzek, M., Bandmann, O.
ID
ZDB-PUB-210325-6
Date
2021
Source
Scientific Reports   11: 6617 (Journal)
Registered Authors
Bandmann, Oliver, Blechman, Janna
Keywords
none
MeSH Terms
  • Cell Differentiation
  • Humans
  • Protein Serine-Threonine Kinases/deficiency*
  • Age Factors
  • Neurogenesis/genetics*
  • Animals, Genetically Modified
  • Dopaminergic Neurons/metabolism*
  • Zebrafish
  • Animals
  • Mesencephalon/metabolism
  • Mesencephalon/pathology
  • Biomarkers
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Parkinson Disease/etiology
  • Parkinson Disease/metabolism
  • Parkinson Disease/pathology
(all 17)
PubMed
33758225 Full text @ Sci. Rep.
Abstract
Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson's disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
pink1sh397/sh397standard conditionsAdult
pink1sh397/sh397standard conditionsAdult
pink1sh397/sh397standard conditionsAdult
pink1sh397/sh397standard conditionsAdult
1 - 4 of 4
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz1701TgTransgenic Insertion
    sh397
      		Point Mutation
      vu298aTgTransgenic Insertion
        1 - 3 of 3
        Show
        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        Fish
        cz1701Tg; vu298aTg
        pink1sh397/sh397
        WT
        1 - 3 of 3
        Show
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab1-thmonoclonalIgG1Mouse
        Ab5-casp3polyclonal
          		Rabbit
          1 - 2 of 2
          Show
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          CreEFGCre
          EGFPEFGEGFP
          mCherryEFGmCherry
          1 - 3 of 3
          Show
          Mapping
          No data available
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          Citation
          Brown, S.J., Boussaad, I., Jarazo, J., Fitzgerald, J.C., Antony, P., Keatinge, M., Blechman, J., Schwamborn, J.C., Krüger, R., Placzek, M., Bandmann, O. (2021) PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons. Scientific Reports. 11:6617.