Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degeneration (original) (raw)
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Astrocytes in Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis, 2021
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by the degeneration of upper and lower motor neurons of the motor cortex, brainstem, and ventral horn of the spinal cord. The role of glial cells in the onset and progression of ALS is increasingly being recognized. Dysfunctional astrocytes, with an atypical and neurotoxic phenotype, in the cerebral cortex and the spinal cord promote neuroinflammation and motor neuron degeneration. Indeed, cortical and spinal cord astrocytes from SOD1G93A (mSOD1) mice are neurotoxic, develop early deficits, and lose their neuro-supportive properties before disease onset. This chapter discusses the contribution of dysfunctional cortical and spinal cord astrocytes in the development and progression of ALS. Differences in astrocyte heterogeneity and reactivity, calcium signaling, neurotransmitters, and in paracrine signaling mechanisms along with implications for novel therapies in ALS are addressed.
A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis
Brain Research Reviews, 2004
A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease. D
Intricate interplay between astrocytes and motor neurons in ALS
Proceedings of the National Academy of Sciences, 2013
ALS results from the selective and progressive degeneration of motor neurons. Although the underlying disease mechanisms remain unknown, glial cells have been implicated in ALS disease progression. Here, we examine the effects of glial cell/motor neuron interactions on gene expression using the hSOD1 G93A (the G93A allele of the human superoxide dismutase gene) mouse model of ALS. We detect striking cell autonomous and nonautonomous changes in gene expression in cocultured motor neurons and glia, revealing that the two cell types profoundly affect each other. In addition, we found a remarkable concordance between the cell culture data and expression profiles of whole spinal cords and acutely isolated spinal cord cells during disease progression in the G93A mouse model, providing validation of the cell culture approach. Bioinformatics analyses identified changes in the expression of specific genes and signaling pathways that may contribute to motor neuron degeneration in ALS, among which are TGF-β signaling pathways. motor neuron gene expression in ALS | reactive astrocyte gene expression in ALS | G93A mouse model of ALS | cell intrinsic and extrinsic effects on gene expression A LS is a late-onset, fatal neurodegenerative disease caused by the selective loss of upper and lower motor neurons in the brain and spinal cord and progressive paralysis of voluntary muscles; death ultimately results from respiratory failure (reviewed in ref. 1). Most ALS cases (∼90%) are sporadic, with an unknown cause, whereas the remaining cases are of familial origin (reviewed in ref.
Focal degeneration of astrocytes in amyotrophic lateral sclerosis
Cell Death and Differentiation, 2008
Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1 G93A transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons. This phenomenon manifests with an early onset and becomes significant concomitant with the loss of motor cells and the appearance of clinical symptoms. Contrary to wild-type astrocytes, mutant hSOD1-expressing astrocytes are highly vulnerable to glutamate and undergo cell death mediated by the metabotropic type-5 receptor (mGluR5). Blocking mGluR5 in vivo slows down astrocytic degeneration, delays the onset of the disease and slightly extends survival in hSOD1 G93A transgenic mice. We propose that excitotoxicity in ALS affects both motor neurons and astrocytes, favouring their local interactive degeneration. This new mechanistic hypothesis has implications for therapeutic interventions.
Astrocyte toxicity in motor neuron disease: progress and future hopes
Future Neurology, 2014
Motor neuron disease or amyotrophic lateral sclerosis is a complex multicompartmental disorder that belongs to a spectrum of neurodegenerative conditions ranging from pure motor neuron disease to frontotemporal dementia. The symptoms and causes of death are determined by the progressive and relentless loss of motor neurons in the motor cortex and spinal cord, resulting in paralysis and respiratory failure. However, in the past 10 years, compelling evidence has demonstrated that astrocytes are also affected by the disease mechanisms and actively contribute to the neurodegenerative process. This review focuses on the pathways that are dysregulated in astrocytes and how they affect the relationship between astrocytes and motor neurons in amyotrophic lateral sclerosis. Ongoing research using new methodologies to unravel the contribution of specific cell types to the disease are predicted to open the door to new therapeutic interventions to slow disease progression in amyotrophic lateral sclerosis.
The role of astrocytes with genetic mutations linked to amyotrophic lateral sclerosis
Neurology Perspectives
Despite advances in the understanding of genetic and molecular aspects of amyotrophic lateral sclerosis (ALS), a rapidly progressive and fatal neurodegenerative disease, the exact pathogenic mechanisms are still largely unknown. For over 20 years, numerous in vitro and in vivo studies have demonstrated the existence of a complex interaction between motor neurons and astrocytes in neurodegeneration. In ALS, astrocytes acquire a reactive phenotype through a phenomenon known as astrogliosis, in which they lose their normal functions and/or acquire highly damaging functions, altering the function and survival of motor neurons. For this review, we set out to analyse the role of astrocytes, particularly in the study of mutations in the SOD1, C9orf72, and TARDBP genes, which are closely related to the pathogenesis of familial ALS. The observations made in this study strongly suggest that the role of astrocytes in ALS is multidimensional, and specifically that astrocytes with different genetic mutations linked to ALS present diverse underlying molecular patterns. Therefore, these cells constitute an extremely promising therapeutic target in the treatment of this neurodegenerative disease.
Journal of Neurochemistry, 2004
Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75 NTR ) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75 NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75 NTR +/+ mouse embryos but had no effect in p75 NTR -/knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75 NTR blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.
Human Molecular Genetics, 2009
Three neurodegenerative diseases affecting upper and/or lower motor neurons have been associated with loss of ALS2/Alsin function: juvenile amyotrophic lateral sclerosis, primary lateral sclerosis and infantileonset ascending hereditary spastic paralysis. The distinct neuronal vulnerability and the role of glia in these diseases remains, however, unclear. We here demonstrate that alsin-depleted spinal motor neurons can be rescued from defective survival and axon growth by co-cultured astrocytes. The astrocytic rescue is mediated by a soluble protective factor rather than by cellular contact. Cortical neurons are intrinsically as vulnerable to alsin depletion as spinal motor neurons but cannot be rescued by co-cultured astrocytes. To our knowledge, these data provide the first example of non-cell-autonomous glial effects in a recessive form of motor neuron disease and a potential rationale for the higher vulnerability of upper versus lower motor neurons in ALS2/Alsin-linked disorders.
Astrocytes from familial and sporadic ALS patients are toxic to motor neurons
Nature …, 2011
Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron (MN) disease with astrocytes implicated as a significant contributor to MN death in familial ALS (fALS) 1-5 . However, these conclusions, in part, derive from rodent models of fALS based upon dominant mutations within the superoxide dismutase 1 (SOD1) gene which account for less than 2% of all ALS cases 2, 4, 5 . Here, we generated astrocytes from post-mortem tissue from both fALS and sporadic ALS (sALS) patients, and show that astrocytes derived from both patient groups are similarly toxic to MNs. In addition, we show that SOD1 is a viable target for sALS, as its knockdown significantly attenuates astrocyte-mediated toxicity towards MNs. Our data highlight astrocytes as a non-cell autonomous component in sALS and provide the first in vitro model system to investigate common disease mechanisms and evaluate potential therapies for sALS and fALS.