ALS: astrocytes take center stage, but must they share the spotlight?

Knott, Andrew B.; Bossy‐Wetzel, Ella

doi:10.1038/sj.cdd.4402241

Cited by 5 publications

(2 citation statements)

References 33 publications

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“…Whereas neurodegenerative disease research typically focuses on neurons, and rightfully so, because neuronal injury is the ultimate cause of the disease symptoms, it is becoming increasingly clear that other cells of the nervous system, including astrocytes and microglia, also play important roles in disease pathology. For example, much of the recent research in ALS has focused on the role of astrocytes in disease onset and progression (85). Studies have reported that activated astrocytes expressing the mutant superoxide dismutase 1 (mSOD1) gene, which causes a form of familial ALS, release a soluble factor that contributes to motor neuron degeneration and death (47,111).…”

Section: Nonneuronal Cell-type Involvementmentioning

confidence: 99%

Nitric Oxide in Health and Disease of the Nervous System

Knott

Bossy‐Wetzel

2009

Antioxidants & Redox Signaling

230

188

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Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration.

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Section: Nonneuronal Cell-type Involvementmentioning

confidence: 99%

Nitric Oxide in Health and Disease of the Nervous System

Knott

Bossy‐Wetzel

2009

Antioxidants & Redox Signaling

230

188

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“…This highly expressed and predominantly cytoplasmic enzyme catalyzes the conversion of superoxide to hydrogen peroxide and oxygen. However, mutant SOD1 causes motor neuron death through a toxic gain-of-function mechanism as opposed to a simple loss-of-function in superoxide scavenging activity (Boillee et al, 2006; Bruijn et al, 2004; Knott and Bossy-Wetzel, 2007; Magrane et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1α

Song

Kincaid

et al. 2013

Neurobiology of Disease

183

148

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Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial dynamics contribute to neurodegeneration, including ALS, previous reports remain conflicted. Here, we report an improved technique to isolate, transfect, and culture rat spinal cord motor neurons. Using this improved system, we demonstrate that mutant SOD1G93A triggers a significant decrease in mitochondrial length and an accumulation of round fragmented mitochondria. The increase of fragmented mitochondria coincides with an arrest in both anterograde and retrograde axonal transport and increased cell death. In addition, mutant SOD1G93A induces a reduction in neurite length and branching that is accompanied with an abnormal accumulation of round mitochondria in growth cones. Furthermore, restoration of the mitochondrial fission and fusion balance by dominant-negative dynamin-related protein 1 (DRP1) expression rescues the mutant SOD1G93A-induced defects in mitochondrial morphology, dynamics, and cell viability. Interestingly, both SIRT3 and PGC-1α protect against mitochondrial fragmentation and neuronal cell death by mutant SOD1G93A. This data suggests that impairment in mitochondrial dynamics participates in ALS and restoring this defect might provide protection against mutant SOD1G93A-induced neuronal injury.

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