Glial cells are thought to be involved in both pathological stages of PD—initiation before neuronal loss and subsequent progressive neurodegeneration reviewed in Halliday and Stevens Suppression of this microglial activation extended survival, suggesting that astrocyte-mediated microglial activation can directly contribute to neurodegeneration Gu et al. An additional contributory factor to astrocyte dysfunction in PD is likely to be the dysregulation of astrocyte-specific functions of recessive PD genes, such as DJ-1 and parkin.
Moreover, the disruption of these astrocyte-specific processes highlights the multiple ways in which astrocytes can function to maintain neuronal health in the face of injury or disease. For example, DJ-1 mutations or deletions that cause a rare form of autosomal recessive parkinsonism Bonifati et al. In an astrocyte—neuron coculture system, down-regulation of DJ-1 compromised the ability of astrocytes to protect neurons against stress inducers.
This neuroprotection was selective for drugs that inhibit mitochondrial complex I, as neuronal death could not be rescued by the addition of antioxidants. Also, neuroprotection in this system was not caused by the release of glutathione or the up-regulation of astrocytic heme oxygenase.
Thus, the role of DJ-1 in astrocyte-mediated neuroprotection is specific to a mechanism involving mitochondrial complex I and is independent of the oxidative stress response. The Nrf2-ARE pathway has been shown to confer protection against oxidative stress in many models of neurodegenerative disease reviewed in Johnson et al. These experiments highlight at least two independent ways in which astrocytes contribute to the maintenance of neuronal health in PD one dependent on DJ-1 and the other via the oxidative stress response.
Another PD-associated gene, parkin , which is thought to function in the ubiquitin proteasome system, may play an astrocyte-specific role in PD. The parkin mutations cause autosomal recessive parkinsonism Kitada et al. By virtue of its ubiquitin ligase activity, parkin is thought to confer protection against stress-induced cell death caused by the unfolded protein response UPR Imai et al. Parkin levels were differentially affected in astrocytes and neurons under conditions of UPR-induced stress— parkin was up-regulated and redistributed in stressed astrocytes but not neurons, suggesting that parkin may have a specialized, astrocyte-specific role under conditions of UPR-induced cellular stress Ledesma et al.
On the basis of these observations, the investigators hypothesized that mutations in parkin lead to astrocytic dysfunction by compromising the ability of astrocytes to cope with UPR-induced stress , and that this dysfunction in astrocytes contributes to neuronal death. Indeed, reactive astrocytes and the UPR have been shown to contribute to neuronal survival in a mouse model of PD Hashida et al.
Astrocyte Pathophysiology in Liver Disease
Interestingly, lowered parkin levels lead to increased susceptibility of astrocytes to cell death MacCormac et al. Reciprocal communication between astrocytes and neurons is important for the maintenance of neuronal health in PD, as exemplified by studies of the Wnt signaling pathway.
ALS is a progressive, invariably fatal neurodegenerative disease that selectively involves the death of upper and lower motor neurons in the brain and spinal cord reviewed in Kiernan et al. Multiple aspects of motor neuron cellular physiology are perturbed and neuromuscular synapses are lost, causing the progressive paralysis of voluntary muscles.
Death ultimately results from respiratory failure.
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Overexpression pathogenic alleles of human SOD1 in mice and rats recapitulates late-onset progressive neurodegenerative disease Gurney et al. The fundamental pathological basis for ALS remains to be determined, as does the specific insult that targets only specific classes of motor neurons for death. However, relevant to this review, glial pathology is observed in all cases of familial and sporadic ALS Neumann et al.
Although ALS is a motor-neuron-specific disease, expression of human ALS-causing mutant genes solely in motor neurons is not sufficient to cause typical ALS-like disease in mice Pramatarova et al. In addition, chimeric mouse experiments revealed that non-neuronal cells expressing mutant ALS-causing SOD1 transgenes can damage nearby WT motor neurons, whereas WT nonneuronal cells can delay degeneration of nearby neurons expressing the mutant SOD1 gene Clement et al.
Thus, nonneuronal cells in the spinal cord can affect the viability of motor neurons in either a positive or negative manner, depending on the genotype of nonneuronal cells. ALS astrocytes have been shown to directly contribute to motor neuron death in vitro. Interestingly, this toxicity was selective to motor neurons, both primary neurons as well those derived from mouse embryonic stem ES cells, and the deleterious effects can be recapitulated by culture medium conditioned by the mutant astrocytes.
Mutant mouse astrocytes are also similarly toxic to human ES-cell-derived motor neurons Di Giorgio et al. Thus, the presence of ALS-associated mutant proteins in astrocytes leads to a motor-neuron-specific non-cell-autonomous toxicity. Of course, the loss of viability of motor neurons in these cell culture experiments could be because of a combination of the loss of positive support by astrocytes and the secretion of toxic factors. Consistent with this view, experiments in cell culture showed that there is extensive cross talk between motor neurons and astrocytes, mediated by an intricate network of signaling pathways, and that mutant protein expression in both neurons and glial cells synergizes to accelerate the death of ALS motor neurons exposed to ALS astrocytes Phatnani et al.
The same strategy was used to implicate mutant microglia Boillee et al. In contrast, reduction of SOD1 levels specifically in motor neurons delayed disease onset, but did not affect disease progression Boillee et al. Thus, the pathophysiology of ALS depends on complex multicellular interactions in the spinal cord.
Transplanting precursors of mutant SOD1 astrocytes into the spinal cord of WT rats has also been shown to lead to the degeneration of motor neurons, which is thought to be mediated in part by the activation of host microglia Papadeas et al. Conversely, transplanting precursors of WT astrocytes into ALS rats not only reduced microgliosis in the spinal cord, but also reduced motor neuron loss and extended survival Lepore et al. Astrocytes from the SOD1 mouse model have been shown to be defective in the uptake of glutamate. The resulting extracellular accumulation of glutamate has been proposed to lead to motor neuron death through excitotoxicity Rothstein et al.
Astrocytes are also thought to exacerbate the vulnerability of motor neurons to excitotoxicity by regulating their ability to modulate expression of the GluR2 subunit of AMPA receptors Van Damme et al. ALS astrocytes have also been shown to have dysfunctional mitochondria Cassina et al.
In vitro and in vivo studies using ALS mice have provided evidence of metabolic dysfunction in ALS astrocytes, particularly in the transporter responsible for the efflux of lactate, an important metabolite for neurons Ferraiuolo et al. These astrocytes have also been shown to activate pronerve growth factor p75—receptor signaling in motor neurons, and thereby contribute to their demise Ferraiuolo et al. ALS causing mutant proteins may also be toxic to the astrocytes themselves.
Astrocytes bearing ubiquitin-positive inclusions and an abnormal morphology, and containing ubiquitin-positive inclusions, have been detected in close proximity to motor neurons before symptom onset Pun et al.
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Finally, astrocytes generated from human iPS cells bearing a familial mutation in TDP43 showed decreased survival Serio et al. In addition, transplanting precursors of mutant TDPoverexpressing mouse astrocytes into WT rat spinal cords did not affect motor neuron survival Haidet-Phillips et al.
Although it has been argued that this lack of toxicity may be because of a difference between mutations in SOD1 and TDP43, transgenic rats expressing human mutant TDP43 in astrocytes did display non-cell-autonomous motor neuron death Tong et al. Thus, the lack of toxicity of iPS-generated human astrocytes in these experiments could be a consequence of differences between primary and iPS-generated astrocytes in the only cases thus far reported. In addition, studies in animal models have revealed a number of astrocyte toxic effects, including 1 the focal loss of the EAAT2 transporter, which is coincident with reactive gliosis and occurs before the loss of motor neurons or onset of symptoms in SOD1 rats Howland et al.
However, increasing the expression of EAAT2 GLT-1 in ALS mice did not delay the onset of paralysis or extend survival, despite protecting neurons from l -glutamate-induced cytotoxicity and cell death in vitro Guo et al. Mitochondrial dysfunction accompanied by an increase in reactive oxygen species ROS from ALS astrocytes has also been proposed as a mechanism that contributes to neurotoxicity Cassina et al. Mitochondria from rat ALS astrocytes are defective in respiratory function, show increased superoxide radical formation, and defects associated with nitro-oxidative damage, whereas treatment of WT astrocytes with mitochondrial inhibitors are toxic to motor neurons in vitro Cassina et al.
Antioxidants and nitric oxide synthase inhibitors ameliorated motor neuron death in vitro Cassina et al. The involvement of astrocytes in the pathology of neurodegenerative diseases is likely caused by a combination of the loss of their normal homeostatic functions and the gain of toxic functions in disease Table 1. Intracellular aggregates are found in astrocytes in various neurodegenerative diseases.
The presence of these aggregates perturbs normal astrocytic functions in various ways that can prove harmful to neuronal viability. The outcome of disrupted astrocyte—neuron communication likely depends on the context, as both astrocytes and neurons are regionally specialized in terms of their morphology and physiology Kimelberg ; Zhang and Barres ; Molofsky et al. For example, neurons may differ in their reliance on astrocytes, depending on their location in the CNS. Neurons may also have specialized requirements, or affect astrocytes in distinct and specific ways, depending on neuronal type.
For example, motor neurons secrete angiogenin, which can be endocytosed by glia, induce RNA cleavage, and alter the astrocyte secretome.
Reactive gliosis in the pathogenesis of CNS diseases - ScienceDirect
Better in vivo tools will certainly be required to assess different types of neurons and their associated, regionally specialized astrocytes in vivo. Although great strides have been made toward understanding how neurons and glia work in concert and how these interactions are disrupted in disease, there is still a long way to go. Additional Perspectives on Glia available at www. Previous Section Next Section.
View this table: In this window In a new window. Table 1. Summary of astrocyte dysfunction in disease. Previous Section. Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23 : — J Neurosci 24 : — Cell Death Differ 18 : — J Neurosci 30 : — Astrocyte-neuron metabolic relationships: For better and for worse. Trends Neurosci 34 : 76 — Cell Mol Neurobiol 31 : — CrossRef Medline Google Scholar. Lancet : — Cell Death Dis 2 : e The mystery and magic of glia: A perspective on their roles in health and disease.
Neuron 60 : — J Cell Mol Med 15 : — The role of astroglia in neuroprotection. Dialogues Clin Neurosci 11 : — Medline Google Scholar. ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron 52 : 39 — Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism.
Science : — Neurobiol Aging 24 : — Acta Neuropathol : — Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci : — Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice.