Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice

Avraham, Karen B.; Sugarman, Heidi; Rotshenker, Shlomo; Groner, Yoram

doi:10.1007/bf01186993

Cited by 72 publications

(33 citation statements)

References 31 publications

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“…Although over-expression of the human SOD protein in transgenic mice appears to be protective after ischemic injury and oxidative stress (33,34), these mice develop a phenotype that simulates premature aging (35)(36)(37), and an increase in SOD1 mRNA and enzymatic activity has been proposed to play an important role in aging (38). Indeed, SOD-1 mRNA levels were shown to be increased in SALS motoneurons in humans (39).…”

mentioning

confidence: 99%

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Raju

Robinson

et al. 1996

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

367

223

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(16,17). To gain further insights into the pathogenesis of FALS, the studies described in this paper were designed to characterize alterations in the neuronal cytoskeleton in the G1H mice and to compare these alterations with those seen in human ALS.MATERIALS AND METHODS Generation of Human SOD1 Transgenic Mice. The G1H line of transgenic mice carry a human SOD1 gene with a Gly-93 -> Ala substitution (G93A). These derive from a described Gl line (13) and have a 40% expansion in transgene copy number (P. Zhai and M.E.G., unpublished data). The G1H mice have been deposited with the Induced Mutant Resource maintained by The Jackson Laboratory (Bar Harbor, ME) under the strain designation C57BL/6J-TgN(SOD1-G93A)lGur. The N1029

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mentioning

confidence: 99%

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Raju

Robinson

et al. 1996

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

367

223

View full text Add to dashboard Cite

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“…In the dismutation reaction the enzyme exhibits a bell-shaped protective effect against free radicals, at higher as well as lower concentrations giving way for increased lipid peroxidation (72,73). The Superoxide dismutase also catalyzes the formation of hydroxyl radical from hydrogen peroxide (74), and the generation of peroxynitrite from nitric oxide and Superoxide which decomposes to the highly reactive hydroxyl free radical (75).…”

Section: Discussionmentioning

confidence: 99%

Markers for Vulnerability in Acute Porphyria. A Hypothesis Paper

Thunell¹,

Andersson²,

Carlmark³

et al. 1995

CCLM

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Summary:Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible relevance to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and renal tissue, and with instances of periodic overload of free radicals giving rise to acute neurologic involvement.Leukocyte concentrations of manganese, calcium, iron and zinc, as well as erythrocyte calcium differed between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly higher levels than the controls.Manganese was found to be the most discriminative component of all the 78 variables investigated, accounting for about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increase, in acute intermittent porphyria, of a manganese associated enzyme, e. g. glutamine synthetase, pyruvate carboxylase or mitochondrial Superoxide dismutase. The best fit into the model considered is provided by a theory focused on Superoxide dismutase, induced in response to Superoxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistent to porphyric manifestations, an increase in potentially prooxidant cellular iron is matched by a proportional increment in manganese, i.e. presumably by a corresponding mitochondrial Superoxide dismutase induction. This mechanism is not operative in porphyric individuals prone to development of neuropsychiatric symptoms.In acute intermittent poiphyria with a history of porphyric illness there is a positive correlation between erythrocyte manganese and serum folate and a negative correlation between leukocyte ferrochelatase activity and serum cobalamin concentration. This may mirror a role of the cobalamin-folate system in the acute porphyric process.

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“…In contrast, transgenic mice expressing high levels of wild-type human SOD1stay healthy, 32 even if several neuromuscular junction abnormalities were described in 24 month-old mice suggesting a premature aging of the nervous system as seen in Down's syndrome. 35 Based on these observations and others, the consensus now is that it is through a toxic gain-of-function effect that mutant SOD1 causes MN degeneration. However, despite 15 years of extensive work on this only available animal model of ALS, the nature of the mutant SOD1 acquired deleterious effect remains elusive.…”

mentioning

confidence: 98%

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Verche¹,

Ikiz²,

Jacquier³

et al. 2010

JRLCR

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Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

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Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice

Cited by 72 publications

References 31 publications

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Markers for Vulnerability in Acute Porphyria. A Hypothesis Paper

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

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