Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations

Kano, Minoru; Takanashi, Masashi; Oyama, Genko; Yoritaka, Asako; Hatano, Taku; Shiba‐Fukushima, Kahori; Nagai, Makiko; Nishiyama, Kazutoshi; Hasegawa, Kazuko; Inoshita, Tsuyoshi; Ishikawa, Keiichi; Akamatsu, Wado; Imai, Yuzuru; Bolognin, Silvia; Schwamborn, Jens Christian

doi:10.1038/s41531-020-00137-8

Cited by 35 publications

(24 citation statements)

References 36 publications

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“…Subsequent studies revealed that functional exhaustion and loss of astroglial homoeostatic support are dominant glial contribution to the PD, and the special definition of “dysfunctional” astrocytes has been introduced 22 , 46 . Furthermore, analysis of post-mortem samples of susbtantia nigra obtained from PD patients demonstrated significant decrease in expression of astroglial markers compared to healthy controls 47 , 48 ; these findings being in general agreement with our concept of astroglial atrophy linked to the disease. Astroglial asthenia, atrophy and loss of homoeostatic and neuroprotective capacities were noted in aging 40 and in various neurodegenerative and neuropsychiatric diseases 23 , 49 ; astroglial atrophy thus represents a defined class of astrogliopathies 50 .…”

Section: Discussionsupporting

confidence: 87%

Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

Ramos-Gonzalez

Mato

Chara

et al. 2021

npj Parkinsons Dis.

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The principal hallmark of Parkinson’s disease (PD) is the selective neurodegeneration of dopaminergic neurones. Mounting evidence suggests that astrocytes may contribute to dopaminergic neurodegeneration through decreased homoeostatic support and deficient neuroprotection. In this study, we generated induced pluripotent stem cells (iPSC)-derived astrocytes from PD patients with LRRK2(G2019S) mutation and healthy donors of the similar age. In cell lines derived from PD patients, astrocytes were characterised by a significant decrease in S100B and GFAP-positive astrocytic profiles associated with marked decrease in astrocyte complexity. In addition, PD-derived astrocytes demonstrated aberrant mitochondrial morphology, decreased mitochondrial activity and ATP production along with an increase of glycolysis and increased production of reactive oxygen species. Taken together, our data indicate that astrocytic asthenia observed in patient-derived cultures with LRRK2(G2019S) mutation may contribute to neuronal death through decreased homoeostatic support, elevated oxidative stress and failed neuroprotection.

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Section: Discussionsupporting

confidence: 87%

Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

Ramos-Gonzalez

Mato

Chara

et al. 2021

npj Parkinsons Dis.

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“…8 f; Supplementary Fig. 9a–c, online resource) [ 38 ]. Development of serial sections with anti-parkin clones A15165 E , - D and - G revealed no immunoreactivity in surviving midbrain neurons of the S. nigra from this ARPD subject.…”

Section: Resultsmentioning

confidence: 99%

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

et al. 2021

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The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.

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“…Patientderived midbrain organoids also showed reduced complexity of midbrain dopaminergic neurons (Smits et al, 2019). Reduced astrocytic activity was shown in 35-day old (1.15 month) midbrain PD organoids, which may be associated with neurodegeneration (Kano et al, 2020). Transcriptomic analysis of brain organoids (at 1.5 and 2 months in culture) derived from iPSC in which LRRK2 mutation was introduced using CRISPR/Cas9 revealed the upregulation of a thioredoxininteracting protein (TXNIP), which was previously reported to be associated with lysosomal dysfunction in α-synucleinoverexpressed cultures.…”

Section: Parkinson's Diseasementioning

confidence: 96%

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

et al. 2021

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Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.

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Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations

Cited by 35 publications

References 36 publications

Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

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