Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.

Graham, J G; Oppenheimer, D. R.

doi:10.1136/jnnp.32.1.28

Cited by 513 publications

(191 citation statements)

References 9 publications

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“…MSA is a sporadic, progressive neurological disorder characterized by parkinsonism, cerebellar dysfunction, autonomic impairment and pyramidal signs (Graham and Oppenheimer, 1969;Gilman et al, 1999;Shults and Gilman, 2003), and ␣-syn-immunoreactive glial cytoplasmic inclusions (GCIs) in oligodendrocytes (Lantos and Papp, 1994;Lantos, 1998;Wakabayashi et al, 1998a;Dickson et al, 1999;Gai et al, 1999;Duda et al, 2000;Dickson, 2001;Goedert, 2001) in several brain regions (Wenning and Jellinger, 2005). These inclusions are accompanied by neuronal loss, astrogliosis, and demyelination (Probst-Cousin et al, 1998;Wenning and Jellinger, 2005).…”

Section: Introductionmentioning

confidence: 99%

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

Shults¹,

Rockenstein²,

Crews³

et al. 2005

J. Neurosci.

224

261

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Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of ␣-synuclein (␣-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of ␣-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) ␣-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of h␣-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of h␣-synimmunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) h␣-syn and ubiquitin, and h␣-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of h␣-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of ␣-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.

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Section: Introductionmentioning

confidence: 99%

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

Shults¹,

Rockenstein²,

Crews³

et al. 2005

J. Neurosci.

224

261

View full text Add to dashboard Cite

show abstract

“…MSA includes the diseases previously referred to as Shy-Drager syndrome, olivopontocerebellar atrophy, and striatonigral degeneration (1,2). Patients with MSA typically develop signs of parkinsonism such as muscle rigidity and tremor, cerebellar dysfunction including ataxia, as well as autonomic nervous system deficits.…”

mentioning

confidence: 99%

Transmission of multiple system atrophy prions to transgenic mice

Watts

Giles

Oehler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

396

397

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Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83 +/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83 +/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83 +/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83 +/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83 +/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.neurodegeneration | bioluminescence imaging | seeding | proteinopathies

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“…It has therefore been proposed that 3-AP may be a model for olivopontocerebellar at rophy with associated parkinsonism (Deutsch et aI., 1989), which is a common feature of multiple system atrophy (Graham and Oppenheimer, 1969). We recently found that systemic administration of 3-nitropropionic acid produces a different pattern of selective neuronal vulnerability, with preferential involvement of the striatum (Beal et aI., 1993a), These results therefore show that agents that act at varying sites in energy production within neurons can produce regionally selective patterns of neuro nal vulnerability.…”

Section: Discussionmentioning

confidence: 99%

3-Acetylpyridine Produces Age-Dependent Excitotoxic Lesions in Rat Striatum

Schulz

Henshaw²,

Jenkins

et al. 1994

J Cereb Blood Flow Metab

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Summary: The effects of 3-acetylpyridine (3-AP) were studied in rat striatum. Striatal injections of 3-AP pro duced dose-dependent lesions. The lesion size was signif icantly increased in 4-and 12-month-old rats compared to l-month-old rats. Coinjection of the competitive N-meth yl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV) or systemic administration of the noncompetitive NMDA antagonist MK-801, the competitive NMDA antagonist L Y274614, or the gluta mate release inhibitor lamotrigine partially but signifi cantly attenuated striatal lesion volume. Consistent with an NMDA receptor-mediated excitotoxic effect, histo logic studies showed that 3-AP lesions result in relative sparing of NADPH-diaphorase neurons. Using freeze clamp, 3-AP resulted in a marked depletion of ATP. Two-3-Acetylpyridine (3-AP), a niacinamide antago nist, is a potent neurotoxin when administered to laboratory animals by single intraperitoneal injec tions. It induces chronic complex motor and behav ioral abnormalities, which may be seen as hyperk inesias, ataxia, tremor of the front legs, tonic cramps, and spontaneous convulsions (Herken, 1968). 3-AP has been reported to induce degenera tion of the inferior olivary neurons, which give rise

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Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.

Cited by 513 publications

References 9 publications

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

Transmission of multiple system atrophy prions to transgenic mice

3-Acetylpyridine Produces Age-Dependent Excitotoxic Lesions in Rat Striatum

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