Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model

Guttenplan, Kevin A.; Weigel, Maya K.; Adler, Drew; Couthouis, Julien; Liddelow, Shane A.; Gitler, Aaron D.; Barres, Ben A.

doi:10.1038/s41467-020-17514-9

Cited by 218 publications

(223 citation statements)

References 39 publications

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“…Activated astrocytes show hypertrophy and express a stereotypical array of cytoskeletal proteins, most prominently GFAP. Liddelow et al [5] reported that induction of a subtype of inflammation-associated reactive astrocytes, that promote death of both neurons and oligodendrocytes, is mediated by activated microglia and others have suggested that this occurs in various neurological diseases [11,17,18]. In the present study, we show that POLG mutations induce astrocytic gliosis in vivo, with concurrent microglial activation ( Fig.…”

Section: Insert the Red Ones From Version In Nature Neuronsciencesupporting

confidence: 72%

“…Recent studies suggested that activated microglia induced astrocytes conversion to the A1 reactive phenotype by releasing Interleukin 1 alpha (IL1α), Tumor Necrosis Factor alpha (TNFα), and the Complement Component Subunit 1q (C1q) [5]. In neurodegenerative states such as AD [16], PD [17], multiple sclerosis (MS) [16] and ALS [18], reactive astrocytes can display both neuroprotective and neurodegenerative functions. The role of astrocyte reactivation and the consequences this has for neuronal homeostasis in mitochondrial diseases has not been explored.…”

Section: Resultsmentioning

confidence: 99%

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Stem cell derived astrocytes withPOLGmutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons

Liang

Kianian

Chen

et al. 2020

Preprint

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The inability to reliably replicate mitochondrial DNA (mtDNA) by mitochondrial DNA polymerase gamma (POLG) leads to a subset of common mitochondrial diseases associated with neuronal death and depletion of neuronal mtDNA. Defining disease mechanisms remains difficult due to the limited access to human tissue. Astrocytes are highly abundant in the brain, playing a crucial role in the support and modulation of neuronal function. Astrocytes also respond to insults affecting the brain. Following damage to the center neural system, which can be hypoxia, inflammation or neurodegeneration, astrocytes become activated, lose their supportive role and gain toxic functions that induce rapid death of neurons and oligodendrocytes. The role of astrocyte reactivation and the consequences this has for neuronal homeostasis in mitochondrial diseases has not been explored. Here, using patient cells carrying POLG mutations, we generated iPSCs and then differentiated into astrocytes. We demonstrated that POLG-astrocytes exhibited both mitochondrial dysfunctions, including loss of mitochondrial membrane potential, energy failure, complex I and IV defects, disturbed NAD+/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG-astrocytes exhibited a toxic effect leading to the death of neurons. Our findings demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. Our studies provide a robust astroglia-neuron interaction model for future investigation of mitochondrial involvement in neurogenesis and neurodegenerative diseases.

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Section: Insert the Red Ones From Version In Nature Neuronsciencesupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Stem cell derived astrocytes withPOLGmutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons

Liang

Kianian

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Astrocytes with SOD1 mutations have been reported to release soluble factors toxic to motor neurons [ 120 ]. IL-1α, TNF-α, and C1q released from microglia drive astrocytes to the neurotoxic phenotype, while reducing reactive astrocytes by inhibiting these factors attenuates the disease progression in the G93A- SOD1 mouse model [ 121 ]. However, little is known about the neuroprotective phenotype of astrocytes in the pathogenesis of ALS.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

Kwon

Koh

2020

Transl Neurodegener

1,411

790

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Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.

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“…Recent advances in astrocyte biology have implicated reactive astrocytes in ALS pathogenesis ( 14 , 22–23 , 29 , 81 , 83 ). However, despite this accumulating evidence ( 5–7 ) and the increased availability of transcriptomic data ( 8 , 27 , 66 ), the molecular determinants of astrocyte gene expression changes that drive reactive transformation have remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytes in ALS display diminished intron retention

Ziff

Taha

Crerar

et al. 2021

Nucleic Acids Research

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Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human-induced pluripotent stem cell (hiPSC)-derived astrocytes carrying ALS-causing mutations in VCP, SOD1 and C9orf72. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell adhesion, stress response and immune activation. This was recapitulated in public-datasets for (i) hiPSC-derived astrocytes stimulated with cytokines to undergo reactive transformation and (ii) in vivo astrocytes following selective deletion of TDP-43. We also re-examined public translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts exhibiting decreased IR. Using nucleocytoplasmic fractionation of VCP mutant astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear transcripts is associated with enhanced nonsense mediated decay and increased cytoplasmic expression of transcripts and proteins regulating reactive transformation. These findings are consistent with a molecular model for reactive transformation in astrocytes whereby poised nuclear reactivity-related IR transcripts are spliced, undergo nuclear-to-cytoplasmic translocation and translation. Our study therefore provides new insights into the molecular regulation of reactive transformation in astrocytes.

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Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model

Cited by 218 publications

References 39 publications

Stem cell derived astrocytes withPOLGmutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons

Stem cell derived astrocytes withPOLGmutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons

Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

Reactive astrocytes in ALS display diminished intron retention

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