Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis

Allen, Simon; Hall, Benjamin; Castelli, Lydia M.; Francis, Laura; Woof, Ryan; Siskos, Alexandros P.; Kouloura, Eirini; Gray, Elizabeth; Thompson, Alexander G.; Talbot, Kevin; Higginbottom, Adrian; Myszczynska, Monika A.; Allen, Chloe; Stopford, Matthew J.; Hemingway, Jordan; Bauer, Claudia S.; Webster, Christopher P; Vos, Kurt J. De; Turner, Martin R; Keun, Hector C.; Hautbergue, Guillaume M.; Ferraiuolo, Laura; Shaw, Pamela J.

doi:10.1093/brain/awy353

Cited by 88 publications

(123 citation statements)

References 74 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: 72%

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: 72%

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Almad

Taga

Joseph

et al. 2020

Preprint

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“…In vitro, cells tend to increase the de novo synthesis to compensate for a recycling deficit, a situation that is not physiologically possible in the brain, where the de novo pathway enzymes are only poorly active (12). This highlights the intrinsic ability of different cell types to mobilize alternative energy supplies to cope with bioenergetics stress -a property termed "metabolic flexibility" (34,35). However, 1 caveat of our study is that it mainly relied upon morphological observations of the neuronal network.…”

Section: Discussionmentioning

confidence: 99%

Rescuing compounds for Lesch-Nyhan disease identified using stem cell–based phenotypic screening

Ruillier¹,

Tournois²,

Boissart³

et al. 2020

JCI Insight

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“…Recent studies have revealed that, in addition to the degeneration of motor neurons, abnormal glial function occurs during ALS progression and contributes significantly to the pathogenesis of ALS. [44][45][46][47] To date, studies on adenosine homeostasis and its regulation in ALS are limited. The enzyme that converts adenosine to AMP (ADK) was found to be upregulated in the reactive astrocytes of patients with ALS 36 (Table 1).…”

Section: Adenosine Homeostasis In Alsmentioning

confidence: 99%

“…36 The suppression of ADK to elevate the aden-osine tone in the spinal cord thus may become a novel therapeutic approach for the development of treatments for ALS, as suggested for epileptic diseases 33,48 and schizophrenia. 49 Conversely, the expression of ADA has been found to be reduced in human astrocytes derived from patients with sporadic or the C9orf72 mutation-evoked ALS 44 ( Table 1). Such a decrease in ADA can lower inosine levels and subsequently impair the adenosine-/inosinemediated bioenergetic capacity (glycolysis) in astrocytes.…”

Section: Adenosine Homeostasis In Alsmentioning

confidence: 99%

“…60,61 Adenosine homeostasis may play an important role in this aspect of ALS pathogenesis because the intracellular adenosine level is critical for the concentration of AMP in cells. A recent study demonstrated that ALS astrocytes express a lower level of ADA and thus fail to produce sufficient amounts of inosine for the production of nicotinamide adenine dinucleotide (NADH) and energy through redox reactions 44,62 (Fig. 1).…”

Section: Adenosine Homeostasis and Amp-activated Protein Kinase In Alsmentioning

confidence: 99%

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Adenosine and Its Receptors as Potential Drug Targets in Amyotrophic Lateral Sclerosis

Chern

Rei

Ribeiro

et al. 2019

Journal of Caffeine and Adenosine Research

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Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that involves the progressive degeneration of the motor neurons of the spinal cord and motor cortex. Severe muscle wasting and bioenergetic disturbances are important hallmarks of ALS. Approximately 90% of all ALS cases are sporadic, while only 10% of ALS cases are familial. As of June 2018, mutations in more than 25 genes have been implicated in ALS. Several experimental models have been designed and established based on these disease-causing ALS genes. To date, riluzole and edaravone are the only available clinical drugs, and they can only slow the disease progression of ALS to some extent. Adenosine is a nucleoside that serves as a homeostatic regulator in the brain. It modulates important pathophysiological functions and the bioenergetic network by controlling receptor-dependent and receptor-independent signaling pathways. In the central nervous system, there are four adenosine receptors (ARs, A 1 , A 2A , A 2B , and A 3), two families of adenosine transporters (concentrative nucleoside transporters and equilibrative nucleoside transporters), and a handful of enzymes that modulate adenosine homeostasis extracellularly and/or intracellularly. Accumulating evidence suggests that the components involved in adenosine homeostasis and ARs are altered dynamically in ALS patients and/or experimental models of ALS. In this review, we highlight recent findings on the role of adenosine in ALS and discuss the potential of ARs and the components involved in adenosine homeostasis as drug targets for this devastating disease.

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Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis

Cited by 88 publications

References 74 publications

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Rescuing compounds for Lesch-Nyhan disease identified using stem cell–based phenotypic screening

Adenosine and Its Receptors as Potential Drug Targets in Amyotrophic Lateral Sclerosis

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