SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries

Rouleau, Guy A.; Clark, Arthur W.; Rooke, Karen; Pramatarova, Albéna; Krizus, Aldis; Suchowersky, Oksana; Julien, Jean‐Pierre; Figlewicz, Denise A.

doi:10.1002/ana.410390119

Cited by 223 publications

(115 citation statements)

References 16 publications

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“…122 Higher expression levels of the same construct with the mouse Thy1.2 promoter (ALZ17 line) also failed to develop NFT or cell loss despite extensive phosphorylation of tau and axonal pathology in central and spinal cord neurons [123][124][125] similar to that seen in spinal cord motor neurons of people with amyotrophic lateral sclerosis. 126 Consistent with the observation of axonopathy, behavioral studies of these mice showed muscle weakness. 124 These two models showed that overexpression of human wild-type 4 repeat tau is insufficient to induce NFT formation, but the somatodendritic localization of tau in neurons does resemble the "pre-tangle" state observed in AD.…”

Section: Tau Transgenic Mouse Modelssupporting

confidence: 78%

Transgenic models of Alzheimer’s disease: Learning from animals

2005

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Summary:As the scope of the problem of Alzheimer's disease (AD) grows due to an aging population, research into the devastating condition has taken on added urgency. Rare inherited forms of AD provide insight into the molecular pathways leading to degeneration and have made possible the development of transgenic animal models. Several of these models are based on the overexpression of amyloid precursor protein (APP), presenilins, or tau to cause production and accumulation of amyloid-␤ into plaques or hyperphosphorylated tau into neurofibrillary tangles. Producing these characteristic neuropathological lesions in animals causes progressive neurodegeneration and in some cases similar behavioral disruptions to those seen in AD patients. Knockout models of proteins involved in AD have also been generated to explore the native functions of these genes and examine whether pathogenesis is due to loss of function or toxic gain of function in these systems. Although none of the transgenic lines models the human condition exactly, the ability to study similar pathological processes in living animals have provided numerous insights into disease mechanisms and opportunities to test therapeutic agents. This chapter reviews animal models of AD and their contributions to developing therapeutic approaches for AD.

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Section: Tau Transgenic Mouse Modelssupporting

confidence: 78%

Transgenic models of Alzheimer’s disease: Learning from animals

2005

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“…However, these additional lines of transgenic mice did not develop prominent NF-rich inclusions in spinal cord motor neurons like the G1H mice. Since another report that appeared after the submission of our paper confirms the presence of NF-rich lesions in the spinal cord of a human patient with FALS due to an I113T SOD1 mutation (51), the neuropathology of authentic FALS in humans and in transgenic mice that express mutant human SOD1 may depend upon the specific mutation in the SOD1 gene.…”

mentioning

confidence: 54%

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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“…Aberrant accumulation of pNF in axonal swellings and somas has been a hallmark of axonal transport disruption in neurodegenerative diseases (Manetto et al, 1988;Munoz et al, 1988;Mizusawa et al, 1989;Sobue et al, 1990;Rouleau et al, 1996;Stokin et al, 2005). Because phosphorylation of neurofilaments has been shown to de- crease active transport of neurofilaments through retinal axons (Jung and Shea, 1999), it is possible that excess pNF within intraocular axons may itself cause progressive declines in RGC gene expression and retrograde transport.…”

Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Soto¹,

Oglesby²,

Buckingham³

et al. 2008

J. Neurosci.

260

236

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Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that ␥-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.

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SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries

Cited by 223 publications

References 16 publications

Transgenic models of Alzheimer’s disease: Learning from animals

Transgenic models of Alzheimer’s disease: Learning from animals

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

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

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