ReviewA role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease originally described by Charcot in 1869, characterized by the selective degeneration of motor neurons from the cortex, brainstem and spinal cord that leads to progressive paralysis and muscle atrophy. Most hypotheses for this selective cell loss have primarily addressed early changes in motor neurons involving oxidative damage, defective cytoskeletal function, protein misfolding and aggregation and excitotoxicity from disruption of extracellular glutamate homeostasis. The degeneration of motor neurons is so blatant that it tends to obscure subtle changes in other cell types that may contribute to ALS. In this review, we will consider the origin of reactive astrogliosis in ALS and how reactive changes in astrocytes may contribute to the progressive nature of ALS.
About 10% of ALS cases show familial inheritance, 20% of which are caused by mutations in the gene encoding copper, zinc superoxide dismutase (SOD-1) [106]. An important clue to the pathogenesis of ALS was provided by the development of several strains of different transgenic animal models of the disease carrying the expression of high levels of mutated SOD-1 genes. Toxicity of mutant SOD-1 involves a dominant gain-of-function rather than simply diminished superoxide-scavenging activity [12], [24], [54]. Spinal motor neurons express high levels of mutant SOD-1 which might explain the selective vulnerability of these neurons. However, current evidence indicates that ALS-linked SOD-1 mutations must be expressed in both neuronal and non-neuronal cells to induce the disease [52], [96]. These findings suggest that interactions between motor neurons and surrounding cells in the spinal cord, nerve or skeletal muscle are required for mutated SOD-1 to initiate neurodegeneration in ALS. Accordingly, a recent study by Clement et al. [23] using chimeric mice composed of mixtures of normal cells and cells expressing ALS mutant SOD-1 showed that motor neuron degeneration is not necessarily associated with the expression of SOD-1 mutations in the motor neuron per se but rather with its expression in a critical number of neighboring neuronal and non-neuronal cells.
Astrocytes represent the largest cell population in the central nervous system (CNS). They closely interact with neurons to provide structural, metabolic and trophic support and actively participate in modulating neuronal excitability and neurotransmission by controlling the extracellular levels of ions and neurotransmitters [13], [41]. In vitro, astrocytes exert potent trophic influences on motor neurons [4], [32], [94] through a variety of proteins and low molecular weight molecules [113], [122], which can be modulated by neuroprotective drugs [94]. In response to injury, astrocytes and microglia display characteristic phenotypic changes characterized as astrocytosis or gliosis. Astrocytes respond to CNS damage by proliferating and adopting a reactive phenotype characterized morphologically by hypertrophic nuclei and cell bodies and elaboration of distinct long and thick processes with increased content of glial fibrillary acidic protein (GFAP). In addition, reactive astrocytes express a wide variety of markers such as cytoskeleton proteins, cell surface and matrix molecules, proteases, protease inhibitors and several growth factors and cytokines [31], [104]. By secreting diffusible factors, damaged neurons or activated astrocytes interact in a complex manner with immune cells and microglia. Activated microglia, in turn, secrete proinflammatory peptides, nitric oxide (NO) and excitotoxins that induce astrocytosis or aggravate neuronal damage, therefore, perpetuating and amplifying a local pathogenic process [51]. However, subtler states of microglia activation may lead to downregulation of the neuroinflammatory process. Since gliosis also occurs in a variety of conditions such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia and Huntington's disease [120], it has long been suggested to be a non-specific response of glial cells to injury and often it is not considered as a primary pathogenic element in ALS. On the other hand, recent evidence indicates the existence of other molecular mechanisms by which activated astrocytes may contribute to either the death of neurons or to their survival in response to damage. Extensive reviews have been recently published about the pathogenesis of ALS [12], [25], [110], the role of microglia and inflammatory cells in ALS [83], and the immune function of astrocytes [31]. In this review, we examine the current evidence that supports an active role of astrocytes contributing both to the induction and to the propagation of motor neuron loss. Understanding of the interactions between neurons and glia in ALS may help to explain the progressive nature of ALS.
Section snippets
Astrocyte pathology in ALS
A strong glial reaction typically surrounds both upper and lower motor neurons in ALS patients [59], [71], [87], [90], [120]. Some degree of gliosis is also found in the lateral descending corticospinal tracts and in the entering points of the tracts into the gray matter [118], thus forming a continuum along the damaged regions. Microglia also proliferate and become activated in these regions, and invading T cells can be found around the capillaries [83]. Reactive astrocytes in ALS show
The origin of astrocytosis in ALS
Symptomatic ALS mice develop a typical “isomorphic” gliosis characterized by proliferative, hypertrophic and globular astrocytes [104]. This type of gliosis has also been described after CNS trauma, epilepsy or axotomy and is mediated by complex signaling between neurons, microglia and astrocytes [82]. However, astrocytes do not respond in a stereotypic manner to all forms of cell or tissue damage. The combination of different mediators such as cytokines, chemokines, growth factors and adhesion
Neurotoxic potential of reactive astrocytes in ALS
Recent studies have emphasized the involvement of astrocyte dysfunction in the pathogenesis of ALS through different synergistic mechanisms.
Astrocytes and motor neuron death
We hypothesize that oxidative stress, occurring in damaged areas undergoing neurodegeneration, disrupts the interactions between motor neuron and astrocytes (Fig. 1). In response to damage, motor neurons can signal the surrounding astrocytes to become activated and upregulate critical genes that may recapitulate the pattern found during development. For example, the re-expression of p75NTR and neuronal NOS may help to determine which neurons survive or undergo apoptosis. In turn, activated
Conclusions
The pathology of ALS is characterized by widespread signs of neuronal and astrocyte dysfunction which account for the appearance of protein aggregates, cytoskeletal abnormalities and mitochondrial swelling. These changes not only affect motor neurons but also the surrounding astrocytes and many interneurons. The origin of this pan-cellular pathology is intriguing and deserves further investigation. Because reactive astrocytes occurring in ALS may spread the phenotypic transformation to
Acknowledgements
This work was supported by the PEDECIBA program; the Linus Pauling Institute, the Environmental Health Sciences Center (ES0021) Oregon State University (USA) and grants from the National Institutes of Health R03 TW006482; P01AT002034; R01 NS033291. We thank Dr. Mark Bevensee for his insightful comments.
References (141)
- et al.
Neurite promoting activity of insulin, insulin-like growth factor I and nerve growth factor on spinal motoneurons is astrocyte dependent
Dev. Brain Res
(1993) - et al.
Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis
Exp. Neurol
(2001) - et al.
Aberrant RNA splicing in sporadic amyotrophic lateral sclerosis
Neuron
(1998) - et al.
Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite
Arch. Biochem. Biophys
(1992) - et al.
Oxidative chemistry of peroxynitrite
Methods Enzymol
(1994) - et al.
Superoxide dismutase and the death of motoneurons in ALS
Trends Neurosci
(2001) - et al.
A neuron-glia signalling network in the active brain
Curr. Opin. Neurobiol
(2001) - et al.
ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions
Neuron
(1997) - et al.
Adaptative responses of spinal astrocytes to oxidative stress
- et al.
Effect of axotomy on perineuronal glial cells in the hypoglossal and dorsal motor vagal nuclei of the cat
Exp. Neurol
(1986)
Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal glial cortical cultures
Neuropharmacology
Motoneurone survival is induced by immature astrocytes from developing avian spinal cord
Dev. Brain Res
Molecular profile of reactive astrocytes: implications for their role in neurologic disease
Neuroscience
Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons
Neuron
Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex
Mol. Brain Res
The precursor pro nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease
Mol. Cell. Neurosci
Stable Mn(III) porphyrins mimic superoxide dismutase in vitro and substitute for it in vivo
J. Biol. Chem
Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man
Exp. Neurol
Selective potentiation of NMDA induced neuronal injury following induction of astrocytic iNOS
Neuron
The biosynthesis of neurotrophin heterodimers by transfected mammalian cells
J. Biol. Chem
S100A6, a calcium and zinc binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis
Biochim. Biophys. Acta
Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons
Brain Res
Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis
Exp. Neurol
Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter in amyotrophic lateral sclerosis
Neuron
S 100beta protein is upregulated in astrocytes and motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis
Neurosci. Lett
Riluzole promotes survival of rat motoneurons in vitro by stimulating trophic activity produced by spinal astrocyte monolayers
Neurosci. Lett
Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide
J. Biol. Chem
Active killing of neurons during development and following stress: a role for p75(NTR) and Fas?
Curr. Opin. Neurobiol
Upregulation of protein tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis
Neurol. Res
Immune reactivity in a mouse model of familial ALS correlates with disease progression
Neurology
Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis
J. Neurochem
The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development
Proc. Natl. Acad. Sci. U. S. A
Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis
Ann. Neurol
CD95–CD95L: can the brain learn from the immune system?
Trends Neurosci
4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes
Glia
Induction of NOS inhibits gap junction permeability in cultures rat astrocytes
J. Neurochem
Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurons and astrocytes in primary cultures
J. Neurochem
Multiple sclerosis patients express increased levels of nerve growth factor in cerebrospinal fluid
Neurosci. Lett
Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis
J. Neurosci. Res
Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism
Glia
A motor neuron-specific epitope and the low-affinity nerve growth factor receptor display reciprocal patterns of expression during development, axotomy, and regeneration
J. Comp. Neurol
Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice
Science
Oxidation versus aggregation—how do SOD1 mutants cause ALS?
Nat. Med
From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS
Nat. Rev., Neurosci
Detection of NGF like activity in human brain tissue: increased levels in Alzheimer's disease
J. Neurosci
Evaluation of neuronal loss, astrocytosis and abnormalities of cytoskeletal components of large motor neurons in the human anterior horn in aging
J. Neural Transm
Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS
Ann. Neurol
Immune function of astrocytes
Glia
Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation
J. Neurosci
Induction of nitric oxide dependent apoptosis in motor neurons by zinc deficient superoxide dismutase
Science
Cited by (264)
Antibiotic-induced gut dysbiosis leads to activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus
2022, Brain, Behavior, and ImmunityNon-cell-autonomous pathogenic mechanisms in amyotrophic lateral sclerosis
2021, Trends in NeurosciencesProgress in progestin-based therapies for neurological disorders
2021, Neuroscience and Biobehavioral ReviewsClinical application of MAO-B PET using <sup>18</sup>F-THK5351 in neurological disorders
2024, Geriatrics and Gerontology InternationalPax6 affects Ras-Raf-ERK1/2 in mouse aging brain
2023, Biogerontology