Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

D’Arrigo, Antonello; Colavito, Davide; Peña-Altamira, Emiliano; Fabris, Michele; Dam, Mauro; Contestabile, Antonio; Leon, A.G. Luqueño

doi:10.1007/s12031-010-9332-2

Cited by 24 publications

(20 citation statements)

References 36 publications

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“…Curiously, the expression of genes involved in cell death pathways was not significantly up-regulated specifically within motor neurons, indicating that the loss of these cells is a late event in the disease [44, 45]. Finally, the pattern of gene expression in the spinal cord of SOD1(G93A) mice at end stage was very similar to that found in post-mortem specimens of human ALS, and affected genes involved in cell death [25, 43, 47] and neuroprotection [43, 44], inflammation [25, 43, 47], proteasome function [25, 42, 43], metabolism [25, 42, 47], cytoskeleton and axonal guidance [25, 42-44, 47] (Fig. 1 ).…”

Section: Transcriptomics For the Analysis Of Als Pathogenesismentioning

confidence: 92%

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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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Section: Transcriptomics For the Analysis Of Als Pathogenesismentioning

confidence: 92%

“…Of note, the expression of the intermediate filament vimentin was consistently found to be up-regulated in several studies [25, 42, 45]. Vimentin plays an important role in the organization of the cytoskeleton and interacts with dynein to mediate neurite outgrowth [46].…”

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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“…However, overexpression of wild type SOD1 in mice does not result in disease, although mitochondrial alterations and subclinical defects are observed at older ages (88). Also, alterations in gene expression in the spinal cord were reported for mutant and WT SOD1 models but not in nontransgenic mice (89). Large aggregates of SOD1 are generally observed in fALS, but have only been reported for a subset of sALS cases (4,5,90), and are not detected by SEDI in sALS (90).…”

Section: Aggregation Arising From Holo Sod1 Is Not Different Frommentioning

confidence: 99%

Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis

Hwang

Stathopulos

Dimmick

et al. 2010

Journal of Biological Chemistry

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Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self-or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1. Amyotrophic lateral sclerosis (ALS)2 is a devastating, rapidly progressive, and invariably fatal neurodegenerative disease, characterized by motor neuron degeneration and paralysis (1). Approximately 10% of ALS cases are familial (fALS), the remaining cases being sporadic (sALS). The familial and sporadic diseases are clinically indistinguishable and so have been proposed to share common disease mechanisms (1). Mutations in copper/zinc superoxide dismutase (SOD1) account for ϳ20% of fALS and represent a major known cause of the disease. It is generally accepted that fALS-linked SOD1 mutations result in a toxic gain of function rather than a loss of function (1). Much attention has focused on toxic protein aggregation as causing ALS, analogous to pathogenic protein aggregation in other neurodegenerative diseases, including Alzheimer, Huntington, Parkinson, and prion diseases (1-5). SOD1 is present in aggregates in motor neurons of SOD1-linked fALS patients (3, 6) and mice models (3, 7-9) and in some sALS patients (4, 5, 10).Mature SOD1 is a homodimeric protein, with each ␤-barrel subunit containing one catalytic copper ion, one structural zinc ion, one intrasubunit disulfide bond, and two free cysteines (11) (see Fig. 1). More than 147 mainly missense mutations throughout the SOD1 structure have been associated with fALS. Aggregation has been reported previously only for immature (metal and/or disulfide deficient) or aberrant forms of SOD1, often under highly destabilizing conditions, which favor aggregation in general (12-19). The relevance to human disease of such aggregation is not known, nor is it known what forms of SOD1 may give rise to or be present in aggregates in patients (20). Mature (holo) SOD1 is a major form of SOD1 in cells for wild type and most mutant SOD1s (11). Although this form has been proposed to be incompatible with aggregation because of its very high stability (15, 21), several studies have rep...

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“…Compared to several other ALS microarrays (Brockington et al 2010; Chen et al 2010; Cox et al 2010; D’arrigo et al 2010; Ferraiuolo et al 2007; Ferraiuolo et al 2011; Gonzalez De Aguilar et al 2008; Jiang et al 2005; Kirby et al 2005; Kudo et al 2010; Vargas et al 2008; Yoshihara et al 2002), we identified five genes from our ≥2-fold change list that have orthologs in SOD1 transgenic mice and human patients with sporadic ALS (Table 1). Sepia is the fly ortholog of mouse glutathione S-transferase omega 1 (O’brien et al 2005) and was up-regulated in 45d flies with G85R in glia and MN+glia but was down-regulated in mouse motoneurons (Kirby et al 2005).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome Profiling Following Neuronal and Glial Expression of ALS-Linked SOD1 inDrosophila

Kumimoto

Fore

Zhang

2013

G3 Genes|Genomes|Genetics

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Amyotrophic lateral sclerosis (ALS) generally is a late-onset neurodegenerative disease. Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial ALS and 2% of all ALS cases. Although a number of hypotheses have been proposed to explain mutant SOD1 toxicity, the molecular mechanisms of the disease remain unclear. SOD1-linked ALS is thought to function in a non–cell-autonomous manner such that motoneurons are critical for the onset, and glia contribute to progression of the disease. Recently, it has been shown in Drosophila melanogaster that expression of human SOD1 in a subset of neuronal cells causes synaptic transmission defects, modified motor function, and altered sensitivity to compounds that induce oxidative stress. Here we used the Gal4-UAS (Upstream Activation Sequence) system to further characterize flies expressing wild-type Drosophila SOD1 (dSOD1) and the mutant human SOD1G85R (G85R) allele in motoneurons and glia. Cell-specific expression of both dSOD1 and G85R was found to influence lifespan, affect sensitivity to hydrogen peroxide, and alter lipid peroxidation levels. To better understand the genetic consequences of G85R expression in motoneurons and glia, we conducted microarray analysis of both young flies (5 days old) and old flies (45 days old) expressing G85R selectively in motoneurons or glia and concurrently in motoneurons and glia. Results from this microarray experiment identified candidate genes for further investigation and may help elucidate the individual and combined contributions of motoneurons and glia in ALS.

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Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

Cited by 24 publications

References 36 publications

Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis

Transcriptome Profiling Following Neuronal and Glial Expression of ALS-Linked SOD1 inDrosophila

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