Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis

Serio, Andrea; Patani, Rickie

doi:10.1002/stem.2758

Cited by 39 publications

(32 citation statements)

References 118 publications

(138 reference statements)

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“…A number of possible pathways of disease have been described, including mitochondrial dysfunction, glutamate excitotoxicity (26,27), problems with autophagy (28) and altered RNA metabolism (29). Furthermore, the death of motor neurons can be "non-cell autonomous, " meaning that other types of cells such as astrocytes, microglia and possibly oligodendrocytes can drive motor neuron death (30,31). There has been considerable research on the type of cell death that occurs in ALS.…”

Section: Introductionmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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Section: Introductionmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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“…Alterations in the white matter (WM) structure have been reported to be more pronounced compared with those in MN structures [3] and have been described also in the perforant path area of ALS patients [4], likely contributing to typical ALS symptoms which include motor and neurological deficits and cognitive decline. Globally, these observations have laid the foundation to consider ALS as a non-cell autonomous disease [5]. Accordingly, a growing amount of evidence has shown that mutant SOD1 expression in non-neuronal cells, mainly astrocytes and microglia, has deleterious effects that contribute to neuronal death [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

Bonfanti

Bonifacino

Raffaele

et al. 2020

IJMS

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.

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“…Mutations in the gene coding for Cu/Zn Superoxide Dismutase 1 (SOD1) constitute around 20% of familial ALS (Chen, Sayana, Zhang, & Le, ; Rosen et al., ). Although defined as motor neuron‐specific disorder, ALS pathogenesis involves non‐neuronal cells, too (Serio & Patani, ). A characteristic feature of neurodegenerative conditions is the concomitant occurrence of neuroinflammation, which is typically characterized by activation of microglia and infiltration of peripheral lymphocytes and macrophages (Liu & Wang, ).…”

Section: Introductionmentioning

confidence: 99%

Interferon‐γ Receptor 1 and GluR1 upregulated in motor neurons of symptomatic hSOD1G93A mice

Sengupta

Adam

et al. 2018

Eur J of Neuroscience

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Motor neurons are markedly vulnerable to excitotoxicity mostly by alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR) stimulation and are principal targets in the neurodegenerative disease Amyotrophic Lateral Sclerosis. Interferon‐gamma (IFN‐γ), a pro‐inflammatory cytokine, can independently cause neuronal dysfunction by triggering calcium influx through a calcium‐permeable complex of IFN‐γ receptor 1(IFNGR1) subunit and AMPAR subunit GluR1. This receptor complex is formed via a non‐canonical neuron‐specific IFN‐γ pathway that involves Jak1/Stat1 and Protein Kinase A. In this study, we explore the expression of the pathway's participants for the first time in the hSOD1G93A Amyotrophic Lateral Sclerosis mouse model. Elevated IFNGR1 and GluR1 are detected in motor neurons of hSOD1G93A symptomatic mice ex vivo, unlike the downstream targets ‐ Jak1, Stat1, and Protein Kinase A. We, also, determine effects of IFN‐γ alone or in the presence of an excitotoxic agent, kainate, on motor neuron survival in vitro. IFN‐γ induces neuronal damage, but does not influence kainate‐mediated excitotoxicity. Increased IFNGR1 can most likely sensitize motor neurons to excitotoxic insults involving GluR1 and/or pathways mediated by IFN‐γ, thus, serving as a potential direct link between neurodegeneration and inflammation in Amyotrophic Lateral Sclerosis.

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Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis

Cited by 39 publications

References 118 publications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

Interferon‐γ Receptor 1 and GluR1 upregulated in motor neurons of symptomatic hSOD1G93A mice

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