Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification

Watanabe, Yasuhiro; Yasui, Kenichi; Nakano, Tetsuo; Doi, Keiko; Fukada, Yasuyo; Kitayama, Michio; Ishimoto, Miho; Kurihara, Saiko; Kawashima, Mika; Fukuda, Hiroki; Adachi, Yoshiki; Inoué, Takao; Nakashima, Kenichiro

doi:10.1016/j.molbrainres.2004.11.019

Cited by 43 publications

(27 citation statements)

References 25 publications

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“…SOD1 L126Z transgenic mice develop an ALS-like phenotype by the age of 300-400 days (17). This observation was later corroborated by other groups in SOD1 L126Z and similar truncation mutations (18)(19)(20). To examine the effect of hwtSOD1 on SOD1 L126Z mice, we developed SOD1 L126Z ͞hwtSOD1 double-transgenic mice and observed an earlier onset of disease and a shorter lifespan than SOD1 L126Z single-transgenic mice (Fig.…”

Section: Results Hwtsod1 Can Hasten Disease or Convert Transgenic Micsupporting

confidence: 78%

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Deng¹,

Shi²,

Furukawa³

et al. 2006

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

386

375

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Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single-and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.crosslinked ͉ disulfide bonds ͉ oxidation ͉ protein aggregation ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of the motor neurons in brain and spinal cord (1). Most of the ALS cases are sporadic, with Ϸ5-10% being familial. The progressive paralysis in ALS usually affects respiratory function, leading to ventilatory failure and death; 50% of patients die within 3 years of onset of symptoms, and 90% die within 5 years. The juvenile form of ALS usually has a prolonged course of two to four decades. There is no known effective treatment for this fatal disease, although marginal delay in mortality has been noted with the drug riluzole (2).Familial ALS can be transmitted as either a dominant or a recessive trait. We and our collaborators have previously shown that mutations in the Cu, Zn-superoxide dismutase gene (SOD1) are associated with Ϸ20% of familial ALS cases (3, 4). The pathogenic mechanisms underlying this disease are still largely unknown. Most, but not all, transgenic mice overexpressing ALS-associated SOD1 mutants develop ALS-like disease (5), and transgenic mice overexpressing human WT SOD1 (hwtSOD1) or SOD1-deficient mice do not develop ALS-like disease (5, 6), suggesting that mutant SOD1 requires a threshold of expression to cause the disease through the gain of a toxic property.Thus far, Ͼ100 mutations, widely distrib...

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Section: Results Hwtsod1 Can Hasten Disease or Convert Transgenic Micsupporting

confidence: 78%

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Deng¹,

Shi²,

Furukawa³

et al. 2006

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

386

375

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“…For immunofluorescence detection of axonally targeted NMNAT1 in brains, Ax-NMNAT1 mice were intracardially perfused with 4% PFA in 0.1 M PBS and brains were postfixed for 24 h, cryopreserved for 3 d, embedded in OCT medium, and subsequently sectioned using a Leica cryostat. Perfused brains of transgenic mice expressing FLAG-tagged SOD1 (kind gift from Prof. Yasuhiro Watanabe, Tottori University, Tottori, Japan) (Watanabe et al, 2005) were cryosectioned and processed as positive controls. Sections (20 m) were mounted onto SuperFrost Plus glass slides (VWR) and incubated overnight in citrate buffer, pH 6.0, at 50°C for antigen retrieval.…”

Section: For Gap43 Mem-⌬nls Nmnat1-flag: 5ј-atcccaagctt-aacttctccccatmentioning

confidence: 99%

“…2, available at www.jneurosci.org as supplemental material) further confirms the lack of high transgene expression. The efficacy of the FLAG antibody was validated using controls from FLAG-tagged wild-type (WF) and frame-shifted (DF) superoxide dismutase transgenic mice (Watanabe et al, 2005) (supplemental Fig. 2, available at www.jneurosci.org as supplemental material).…”

Section: Expression Of Ax-nmnat1 Transgene At Low Dosesmentioning

confidence: 99%

Targeting NMNAT1 to Axons and Synapses Transforms Its Neuroprotective PotencyIn Vivo

Babetto¹,

Beirowski²,

Janečková³

et al. 2010

J. Neurosci.

113

101

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Axon and synapse degeneration are common components of many neurodegenerative diseases, and their rescue is essential for effective neuroprotection. The chimeric Wallerian degeneration slow protein (Wld S ) protects axons dose dependently, but its mechanism is still elusive. We recently showed that Wld S acts at a non-nuclear location and is present in axons. This and other recent reports support a model in which Wld S protects by extranuclear redistribution of its nuclear NMNAT1 portion. However, it remains unclear whether cytoplasmic NMNAT1 acts locally in axons and synapses or at a non-nuclear site within cell bodies. The potency of axon protection by non-nuclear NMNAT1 relative to Wld S also needs to be established in vivo. Because the N-terminal portion of Wld S (N70) localized to axons, we hypothesized that it mediates the trafficking of the NMNAT1 portion. To test this, we substituted N70 with an axonal targeting peptide derived from amyloid precursor protein, and fused this to NMNAT1 with disrupted nuclear targeting. In transgenic mice, this transformed NMNAT1 from a molecule unable to inhibit Wallerian degeneration, even at high expression levels, into a protein more potent than Wld S , able to preserve injured axons for several weeks at undetectable expression levels. Preventing NMNAT1 axonal delivery abolished its protective effect. Axonally targeted NMNAT1 localized to vesicular structures, colocalizing with extranuclear Wld S , and was cotransported at least partially with mitochondria. We conclude that axonal targeting of NMNAT activity is both necessary and sufficient to delay Wallerian degeneration, and that promoting axonal and synaptic delivery greatly enhances the effectiveness.

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“…A new transgenic line, the SOD1 L126 delTT mouse, was generated by expressing a truncated form of SOD1 that leads to pathological features and motor neuron degeneration similar to that observed in ALS [53]. Recently, Fukada et al .…”

Section: Transcriptomics For the Analysis Of Als Pathogenesismentioning

confidence: 99%

Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

Henriques

Aguilar²

2011

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Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease characterized by the loss of upper and lower motor neurons, progressive muscle atrophy, paralysis and death, which occurs within 2-5 years of diagnosis. Most cases appear sporadically but some are familial, usually inherited in an autosomal dominant pattern. It is postulated that the disease results from the combination of multiple pathogenic mechanisms, which affect not only motor neurons but also non-neuronal neighboring cells. Together with the understanding of this intriguing cell biology, important challenges in the field concern the design of effective curative treatments and the discovery of molecular biomarkers for early diagnosis and accurate monitoring of disease progression. During the last decade, transcriptomics has represented a promising approach to address these questions. In this review, we revisit the major findings of the numerous studies that analyzed global gene expression in tissues and cells from biopsy or post-mortem specimens of ALS patients and related animal models. These studies corroborated the implication of previously described disease pathways, and investigated the role of new genes in the pathological process. In addition, they also identified gene expression changes that could be used as candidate biomarkers for the diagnosis and follow-up of ALS. The limitations of these transcriptomics approaches will be also discussed.

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Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification

Cited by 43 publications

References 25 publications

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Targeting NMNAT1 to Axons and Synapses Transforms Its Neuroprotective PotencyIn Vivo

Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

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