C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis

Allen, Simon; Hall, Benjamin; Woof, Ryan; Francis, Laura; Gatto, Noemi; Shaw, Andrew; Myszczynska, Monika A.; Hemingway, Jordan; Coldicott, Ian; Willcock, Amelia; Job, Lucy; Hughes, Rachel M; Boschian, Camilla; Bayatti, Nadhim; Heath, Paul R.; Bandmann, Oliver; Mortiboys, Heather; Ferraiuolo, Laura; Shaw, Pamela J.

doi:10.1093/brain/awz302

Cited by 62 publications

(71 citation statements)

References 99 publications

(128 reference statements)

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“…In vitro evidence from human induced astrocytes from C9orf72 patients suggests that dysregulation of astrocyte miRNA involved in the regulation of axonal maintenance genes impairs extracellular trafficking between astrocytes and neurons, leading to motor neuron death (Varcianna et al, 2019). Other recent studies find that induced astrocytes from C9orf72 positive fALS and sporadic ALS individuals exhibit loss of metabolic flexibility, in particular in glucose and fructose metabolism (Allen et al, 2019). A major point of future interrogation lies in understanding how impaired astrocyte function activity may particularly increase susceptibility for motor neuron degeneration.…”

Section: Glial Reactivitymentioning

confidence: 99%

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2019

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G 4 C 2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G 4 C 2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G 4 C 2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular

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Section: Glial Reactivitymentioning

confidence: 99%

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2019

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“…Moreover, it was shown previously that mitochondrial defects in muscles resulted in degeneration of neuromuscular junctions [133]. Furthermore, recent discoveries showed that defects in adenosine, fructose and glycogen metabolism in induced astrocytes from C9ORF72-ALS and sALS patients were linked to a higher susceptibility to adenosine-induced toxicity and defective metabolic flexibility in motor neurons and astrocytes respectively [134,135].…”

Section: In Vivo Metabolic Tracingmentioning

confidence: 97%

“…Given that astrocytes and oligodendrocytes provide lactate to motor neurons, which is assumed to contribute to neuronal survival, a decrease in glycolysis in these glial cells could result in a decrease in the oxidative phosphorylation in motor neurons due to a decrease in lactate as energy substrate [82,83,132,162]. Moreover, the findings linking astrocyte and motor neuron toxicity in C9ORF72-ALS and sALS to the metabolic dysregulation of astrocytes together with the detrimental effects of mitochondrial defects in muscles on neuromuscular junctions underline the possibility of motor neuron extrinsic metabolic defects in ALS [133][134][135]. Indeed, in vivo metabolomics potentially capture the motor neuron microenvironment in a better way compared to in vitro metabolomics and could therefore lead to new insights into the metabolic defect in ALS.…”

Section: In Vivo Metabolic Tracingmentioning

confidence: 99%

Existing and Emerging Metabolomic Tools for ALS Research

Germeys

Vandoorne

Bercier

et al. 2019

Genes

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Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies.

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“…158 Moreover, we have recently reported an altered metabolic profile in induced astrocytes from C9ALS patients, where defects in nucleoside, glycogen, pyruvate and fructose metabolism corresponded to a decrease in metabolic flexibility. 137,160 It appears that C9orf72 induced astrocytes have a decreased capacity to mobilize glycogen, an aspect that could reduce glucose levels and consequently minimize ATP production in times of bioenergetic stress. 137 Even though the aforementioned studies investigate two separate metabolic pathways, FAO and glycolysis, in genetically distinct models of ALS, their findings emphasize the crucial role of metabolic flexibility in ALS, and capture the attempt of the cells to mitigate metabolic stress in order to restore energy homeostasis.…”

Section: The Potential Contribution Of Glycolysis and Fatty Acid Oxidmentioning

confidence: 99%

“…137,160 It appears that C9orf72 induced astrocytes have a decreased capacity to mobilize glycogen, an aspect that could reduce glucose levels and consequently minimize ATP production in times of bioenergetic stress. 137 Even though the aforementioned studies investigate two separate metabolic pathways, FAO and glycolysis, in genetically distinct models of ALS, their findings emphasize the crucial role of metabolic flexibility in ALS, and capture the attempt of the cells to mitigate metabolic stress in order to restore energy homeostasis. Both pathways have the capacity to modulate the activity of the other, but considering the complex downstream signaling cascades influenced by these major energy generating-systems, it remains an open question whether increasing the activity in one to the detriment of the other is beneficial in the long term or not ( Figure 6).…”

Section: The Potential Contribution Of Glycolysis and Fatty Acid Oxidmentioning

confidence: 99%

Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis

Floare

Allen

2020

J Exp Neurosci

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).

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C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis

Cited by 62 publications

References 99 publications

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Existing and Emerging Metabolomic Tools for ALS Research

Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis

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