Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis

Pehar, Mariana; Vargas, Marcelo R.; Cassina, Patricia; Barbeito, Ana G.; Beckman, Joseph S.; Barbeito, Luis

doi:10.1159/000089619

Cited by 71 publications

(51 citation statements)

References 182 publications

(95 reference statements)

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“…This is concordant with other studies showing that astrocytosis in G93A mice is triggered by motor neuron degeneration [33] and occurs pri-or to symptom onset [34] . Cells injected at this presymptomatic time point probably could unfold their neuroprotective potential much better because degeneration of motor neurons had not progressed yet.…”

Section: Histological Evaluationsupporting

confidence: 93%

Intraspinal Injection of Human Umbilical Cord Blood-Derived Cells Is Neuroprotective in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Knippenberg¹,

Thau²,

Schwabe³

et al. 2011

Neurodegener Dis

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Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons in the spinal cord, brain stem and motor cortex and has only marginal therapeutic options. Adult stem cells have recently come into the focus of neurological research. While replacement of motor neurons by stem cells currently appears not feasible, there is evidence that non-neuronal cells can be neuroprotective. Objective: Therefore, we evaluated the effects of direct intraspinal administration of human umbilical cord blood cells in a G93A transgenic mouse model of ALS before (day 40) and after symptom onset (day 90). Methods: Treatment effects were assessed by survival analysis, behavioral tests, histological and biochemical analyses. Results: Treatment at early stages increased survival, led to significant improvements in motor performance and significantly reduced motor neuron loss and astrogliosis in the spinal cord. Interestingly females tended to respond better to treatment than males. Conclusion: This study confirms the neuroprotective potential of human umbilical cord blood cells and encourages further investigations.

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Section: Histological Evaluationsupporting

confidence: 93%

Intraspinal Injection of Human Umbilical Cord Blood-Derived Cells Is Neuroprotective in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Knippenberg¹,

Thau²,

Schwabe³

et al. 2011

Neurodegener Dis

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“…Schwann cells [80] and astrocytes [81,82]). Nevertheless, acute inhibition [83][84][85] or knockdown of p75 [86] in the SOD1 G93A mice was shown to reduce the neurodegeneration. Furthermore, the p75 ICD was found to associate with the retrograde motor dynein in the nerves from these mice, suggesting that it is retrogradely transported in the neurons [76].…”

Section: Retrograde Degenerative Signalingmentioning

confidence: 99%

Retrograde apoptotic signaling by the p75 neurotrophin receptor

Pathak

Carter

2017

Neuronal Signaling

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Neurotrophins are target-derived factors necessary for mammalian nervous system development and maintenance. They are typically produced by neuronal target tissues and interact with their receptors at axonal endings. Therefore, locally generated neurotrophin signals must be conveyed from the axon back to the cell soma. Retrograde survival signaling by neurotrophin binding to Trk receptors has been extensively studied. However, neurotrophins also bind to the p75 receptor, which can induce apoptosis in a variety of contexts. Selective activation of p75 at distal axon ends has been shown to generate a retrograde apoptotic signal, although the mechanisms involved are poorly understood. The present review summarizes the available evidence for retrograde proapoptotic signaling in general and the role of the p75 receptor in particular, with discussion of unanswered questions in the field. In-depth knowledge of the mechanisms of retrograde apoptotic signaling is essential for understanding the etiology of neurodegeneration in many diseases and injuries.

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“…Activated microglia, in turn, secrete proinflammatory peptides, nitric oxide (NO), and excitotoxins that further induce astrocytosis or aggravate neuronal damage, therefore perpetuating and amplifying a local pathogenic process (56). Recent evidence indicates the existence of mechanisms by which activated astrocytes may contribute either to the death of neurons or to their survival in response to damage (7,106,132). Understanding these processes and the interaction between neurons and glia may help to explain the induction and the propagation of motor-neuron loss in ALS.…”

Section: A Role For Astrocytes and Impairment Of The Astroglial Glutamentioning

confidence: 99%

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Foran

Trotti²

2009

Antioxidants & Redox Signaling

255

141

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Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis

Cited by 71 publications

References 182 publications

Intraspinal Injection of Human Umbilical Cord Blood-Derived Cells Is Neuroprotective in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Intraspinal Injection of Human Umbilical Cord Blood-Derived Cells Is Neuroprotective in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Retrograde apoptotic signaling by the p75 neurotrophin receptor

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

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