Selective vulnerability and mechanism of degeneration in a mouse model of amyotrophic lateral sclerosis.
Item
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Title
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Selective vulnerability and mechanism of degeneration in a mouse model of amyotrophic lateral sclerosis.
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Identifier
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AAI9830742
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identifier
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9830742
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Creator
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Morrison, Brett Michael.
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Contributor
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Adviser: John H. Morrison
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience | Health Sciences, Medicine and Surgery | Health Sciences, Pathology | Health Sciences, Immunology
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Abstract
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Transgenic mice with a mutation in the superoxide dismutase (SOD-1) gene, corresponding to a mutation observed in familial amyotrophic lateral sclerosis (ALS), display progressive loss of motor function and provide a valuable model of ALS. Several mechanisms of degeneration have been proposed, including alterations of neurofilament and increased intracellular calcium related to excitotoxicity. We hypothesize that a neuro-chemical profile exists that renders specific subpopulations of neurons vulnerable to these degenerative mechanisms, and that this vulnerability profile will shed light on these mechanisms.;SOD-1 transgenic mice develop loss of motor neurons and interneurons, somatic accumulations of neurofilament, and astrocytosis in the spinal cord coincident with the onset of symptoms. The neuron loss is less than 50% in endstage SOD-1 transgenic mice, and we were interested in whether specific proteins localize preferentially to vulnerable or non-vulnerable neurons. Two proteins hypothesized to play a role in the pathogenesis of ALS are calbindin and neurofilament. We found that calbindin-immunoreactive neurons do not degenerate in SOD-1 transgenic mice, suggesting that elevated intracellular calcium, perhaps secondary to excitotoxicity, may be a component of the mechanism of ALS degeneration. In contrast to calbindin, neurofilament is present within a vulnerable population of neurons, and the magnitude of both motor neuron and interneuron loss is predicted by the percentage of these neuronal populations that contain neurofilament. These results suggest that the neurochemical profile (i.e., presence of neurofilament and absence of calbindin) of a neuron is a more dominant determinant of vulnerability than connectivity.;The absence of GluR2 from AMPA receptors on motor neurons may contribute to their excitotoxic degeneration, as AMPA receptors that lack GluR2 are calcium-permeable. We determined, however, that there is no correlation between vulnerability and the presence or absence of GluR2 in the spinal cord. In addition, we also found that the cellular and synaptic distribution of GluR2 is unaltered in SOD-1 transgenic mice. Therefore, GluR2 does not appear to be a determinant of cellular vulnerability, nor does the disruption of GluR2 appear to be a component of the mechanism of degeneration in this model of ALS.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
