Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

Birger, Anastasya; Ben-Dor, Israel; Ottolenghi, Miri; Turetsky, Tikva; Gil, Yaniv; Sweetat, Sahar; Perez, Liat; Belzer, Vitali; Casden, Natania; Steiner, Debora; Izrael, Michal; Galun, Eithan; Feldman, Eva L.; Behar, Oded; Reubinoff, Benjamin

doi:10.1016/j.ebiom.2019.11.026

Cited by 135 publications

(135 citation statements)

References 55 publications

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“…Using a fully humanized, spinal cord specific, co-culture platform to study ALS astrocyte/MN interactions, we were able to recapitulate previous studies 24,27,[63][64][65][66][67] showing that ALS hiPSC-A were toxic to hiPSC-MN in co-culture with several FALS and SALS lines. To identify specifically whether toxicity was mediated by the extracellular release of relevant toxic factors, we used a transwell system separating ALS hiPSC-A from hiPSC-M.…”

Section: Discussionsupporting

confidence: 71%

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Almad

Taga

Joseph

et al. 2020

Preprint

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Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and may contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In human ALS tissues and biofluids, we observe that higher levels of Cx43 correlate with accelerated disease progression. Using human iPSC-derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we show that Cx43 is upregulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We then demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes, during a specific temporal window, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Our data identify Cx43 hemichannels as novel conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.

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Section: Discussionsupporting

confidence: 71%

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Almad

Taga

Joseph

et al. 2020

Preprint

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“…Interestingly, SOD1 and TDP-43 were dispensable in this process, and death was triggered by soluble toxic factors. Another report showed that induced pluripotent stem cell-derived astrocytes from C9orf72 patients exerted motoneuron toxicity that correlated with elevated astrocytic oxidative stress, reduced antioxidant capacity and senescence ( Birger et al , 2019 ). Interestingly, both necroptosis and oxidative stress have a potential to boost an inflammatory response, which can further increase astrocytic neurotoxicity.…”

Section: Glial Cells As Key Contributors To Als Pathogenesismentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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“…Although there is an argument whether hyper‐ or hypoexcitability participates in the pathology of ALS, it is obvious that electrophysiological variations contain a minimal phenotype in ALS models (Hawrot et al, 2020). Recently, Ustyantseva et al (2020) generated an iPSC line from PBMC of the patient with SOD1 Asp90Ala mutation utilizing episomal vectors, and Birger et al (2019) obtained iPSC‐derived astrocytes from ALS patients with C9orf72 mutations. Birger et al found that a reduction in the secretion of various antioxidant proteins in MNs due to soluble factors secreted by C9‐mutated astrocytes played a key role in MNs apoptosis in ALA patients.…”

Section: Neurodegenerative Disease Modeling Using Ipscsmentioning

confidence: 99%

“…The results show that oxidative stress resulting from any impairment in C9‐astrocytes has a toxic effect on MNs that possibly leads to neurodegeneration. Importantly, the findings show that therapeutic approaches in familial ALS in addition to MNs can target astrocytes to decrease nervous system damage (Birger et al, 2019). In another study, Bursch et al (2019) showed that iPSC‐derived MNs from ALS patients carrying a mutation in C9orf72, SOD1, and TDP43 demonstrate some mutation‐specific modifications in glutamate receptor features in combination with calcium dynamics, supporting ALS pathogenesis.…”

Section: Neurodegenerative Disease Modeling Using Ipscsmentioning

confidence: 99%

Induced pluripotent stem cells (iPSCs) as game‐changing tools in the treatment of neurodegenerative disease: Mirage or reality?

Yousefi

Abdollahii

Kouhbanani

et al. 2020

Journal Cellular Physiology

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Based on investigations, there exist tight correlations between neurodegenerative diseases' incidence and progression and aberrant protein aggregreferates in nervous tissue. However, the pathology of these diseases is not well known, leading to an inability to find an appropriate therapeutic approach to delay occurrence or slow many neurodegenerative diseases' development. The accessibility of induced pluripotent stem cells (iPSCs) in mimicking the phenotypes of various late‐onset neurodegenerative diseases presents a novel strategy for in vitro disease modeling. The iPSCs provide a valuable and well‐identified resource to clarify neurodegenerative disease mechanisms, as well as prepare a promising human stem cell platform for drug screening. Undoubtedly, neurodegenerative disease modeling using iPSCs has established innovative opportunities for both mechanistic types of research and recognition of novel disease treatments. Most important, the iPSCs have been considered as a novel autologous cell origin for cell‐based therapy of neurodegenerative diseases following differentiation to varied types of neural lineage cells (e.g. GABAergic neurons, dopamine neurons, cortical neurons, and motor neurons). In this review, we summarize iPSC‐based disease modeling in neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Moreover, we discuss the efficacy of cell‐replacement therapies for neurodegenerative disease.

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Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

Cited by 135 publications

References 55 publications

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Induced pluripotent stem cells (iPSCs) as game‐changing tools in the treatment of neurodegenerative disease: Mirage or reality?

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