Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis

Schiffer, Davide; Cordera, Susanna; Cavalla, Paola; Migheli, Antonio

doi:10.1016/0022-510x(96)00073-1

Cited by 225 publications

(161 citation statements)

References 29 publications

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“…These findings have been confirmed numerous times both in humans and mutant SOD1 (mSOD1) mouse models 43, 44, 45. Microglia came under thorough scrutiny for their possible involvement in disease pathogenesis.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 72%

“…Astrocytic activation is also present in multiple regions of the spinal cord and brain in ALS patients and mouse models,44, 46, 63 and is associated with motor neuron loss 44, 46, 64. Importantly, reduction of mSOD1 restricted to astrocytes slowed disease progression, in a similar manner as with microglial restricted mSOD1 reduction, likely attributed to inhibition of microglial activation 64.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 96%

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New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 72%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 96%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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“…These pathological hallmarks provide a unifying description of a range of conditions defined as TDP-43 proteinopathies (4). At present, >30 mutations in the TDP-43 gene (TARDBP) have been linked to familial ALS (fALS) (5), strongly suggesting a causative role for TDP-43 in the pathogenesis of ALS.Accumulating evidence from experimental systems implicating non-cell-autonomous mechanisms in ALS has highlighted the importance of the glial cellular environment to motor neuron (MN) degeneration (1,3,(6)(7)(8)(9). In vivo rodent models of ALS with lineage-specific SOD1 expression have particularly influenced our understanding of the nonneuronal contribution to disease progression.…”

mentioning

confidence: 99%

“…In vivo rodent models of ALS with lineage-specific SOD1 expression have particularly influenced our understanding of the nonneuronal contribution to disease progression. Glial expression of mutant SOD1 cannot initiate MN disease on its own, but is necessary for disease progression (6,7). Furthermore, astrogliosis precedes MN degeneration in some animal models and is a dominant feature of all human ALS pathology (4,6,10).…”

mentioning

confidence: 99%

“…Glial expression of mutant SOD1 cannot initiate MN disease on its own, but is necessary for disease progression (6,7). Furthermore, astrogliosis precedes MN degeneration in some animal models and is a dominant feature of all human ALS pathology (4,6,10). Collectively, these observations highlight the need to better understand the nature of astroglial pathology in ALS.…”

mentioning

confidence: 99%

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Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Serio

Bilican

Barmada

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

307

331

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Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNAbinding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALScausing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies.glia | motor neuron disease | disease modeling T ransactive response DNA-binding protein (TDP-43) is the major component of ubiquitinated cytoplasmic and nuclear inclusions in neurons and astroglia in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP) (1-3). These pathological hallmarks provide a unifying description of a range of conditions defined as TDP-43 proteinopathies (4). At present, >30 mutations in the TDP-43 gene (TARDBP) have been linked to familial ALS (fALS) (5), strongly suggesting a causative role for TDP-43 in the pathogenesis of ALS.Accumulating evidence from experimental systems implicating non-cell-autonomous mechanisms in ALS has highlighted the importance of the glial cellular environment to motor neuron (MN) degeneration (1,3,(6)(7)(8)(9). In vivo rodent models of ALS with lineage-specific SOD1 expression have particularly influenced our understanding of the nonneuronal contribution to disease progression. Glial expression of mutant SOD1 cannot initiate MN disease on its own, but is necessary for disease progression (6, 7). Furthermore, astrogliosis precedes MN degeneration in some animal models and is a dominant feature of all human ALS pathology (4, 6, 10). Collectively, these observations highlight the need to better understand the nature of astroglial pathology in ALS. Combining developmental neurobiological principles of cell fate determination with human induced pluripotent stem cell (iPSC) lines derived from patients carrying ALS disease-causing mutations may provide important insights into astroglia pathology.We recently generated human MNs from iPSC lines derived from a fALS patient and demonstrated that the M337V TDP-43 mutation confers cell-autonomous toxicity to MNs (11). More...

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Time course of neuropathology in the spinal cord of G86R superoxide dismutase transgenic mice

et al. 1998

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Transgenic mice with a G86R mutation in the mouse superoxide dismutase (SOD-1) gene, which corresponds to a mutation observed in familial amyotrophic lateral sclerosis (ALS), display progressive motor dysfunction leading to paralysis and premature death. In endstage SOD-1 transgenic mice, there is marked loss of spinal motor neurons and interneurons, accumulation of phosphorylated neurofilament inclusions, and reactive astrocytosis. The present study details the time course and ultrastructural appearance of these pathologic changes and correlates the timing of these events with the behavioral symptoms. There is no significant reduction in the number of total neurons, motor neurons, or interneurons in the ventral spinal cord of presymptomatic mice, as compared to age-matched control mice. In contrast, there is a significant reduction in the number of total neurons (-23.5%), motor neurons (-28.9%), and interneurons (-23.5%) in symptomatic SOD-1 transgenic mice. This neuron loss correlates temporally with the onset of reactive astrocytosis and the appearance of phosphorylated neurofilament inclusions. The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degeneration in the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal cord. In addition, the late onset and rapid progression of neuron loss suggest that a toxic property is accumulating while the SOD-1 transgenic mice are presymptomatic, and that this toxic property must reach a threshold level before the onset of neuronal degeneration.

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Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis

Cited by 225 publications

References 29 publications

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Time course of neuropathology in the spinal cord of G86R superoxide dismutase transgenic mice

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