Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach

Deng, Han Xiang; Jiang, Hujun; Fu, Rui; Zhai, Hong; Shi, Yong Ying; Liu, Erdong; Hirano, Masashi; Canto, Mauro C. Dal; Siddique, Teepu

doi:10.1093/hmg/ddn368

Cited by 7 publications

(11 citation statements)

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“…The FUS pathology in spinal cord has been previously evaluated using immunostaining, and FUS‐positive inclusions have not been identified in SALS and non‐FUS ALS cases 8, 25, 26. In our previous studies of SOD1 inclusions in spinal cord of SOD1‐linked FALS patients and SOD1 transgenic mice, we observed that antigen retrieval methodology played an essential role in detection of SOD1 inclusions in lower motor neurons,21, 22 especially in some human cases (unpublished data). We compared 3 antigen retrieval protocols: boiling and microwave, which are most commonly used, and high‐pressure decloaking chamber.…”

Section: Resultsmentioning

confidence: 98%

“…Immunohistochemical analysis of the spinal cord sections revealed that FUS‐immunoreactive inclusions were present in some of the surviving spinal anterior horn neurons from all 52 SALS cases, 12 SOD1‐negative FALS cases, and 10 ALS/dementia cases (Fig 2 and Supplementary Fig 1), but not in the 4 FALS cases with SOD1 mutations. Previous studies have demonstrated that SOD1/ubiquitin‐positive inclusions in spinal motor neurons are a pathological hallmark in ALS patients with SOD1 mutations and in transgenic mice overexpressing mutant SOD1 18, 22. Supporting the notion that the FUS‐positive inclusions are absent in SOD1‐linked ALS, we found that the ubiquitin‐positive inclusions in spinal neurons were FUS‐negative in patients with SOD1 G85R or SOD1 A4V mutation and in the transgenic mice overexpressing SOD1 G93A and SOD1 L126Z (Supplementary Fig 2) 21, 23.…”

Section: Resultsmentioning

confidence: 99%

“…We compared 3 antigen retrieval protocols: boiling and microwave, which are most commonly used, and high‐pressure decloaking chamber. We found that antigen retrieval using the high‐pressure decloaking chamber was the most efficient in detection of SOD1 inclusions, and have therefore adopted this protocol as the routine method for antigen retrieval 21, 22. Because other studies failed to show FUS pathology in SALS using microwave protocol for antigen retrieval,8, 25, 26 we assumed that in addition to the sensitivity of the antibodies, antigen retrieval methodology may be an important factor for influencing the detection of FUS‐positive inclusions.…”

Section: Resultsmentioning

confidence: 99%

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FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

Deng

Zhai

Bigio

et al. 2010

Annals of Neurology

290

177

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Objective Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5-10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4-5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated. Methods Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n=52), ALS with dementia (ALS/dementia, n=10) and FALS (n=16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration (FTLD) were also studied. In total, 100 cases were studied. Results FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all sporadic and familial ALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62 and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions and an unusual antigen retrieval appeared to be important for detection of the skein-like FUS inclusions. Interpretation Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia and related disorders. Our data also indicate that SOD1-linked ALS may have a distinct pathogenic pathway from SALS and other types of FALS.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

Deng

Zhai

Bigio

et al. 2010

Annals of Neurology

290

177

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“…Several previous studies have established that co‐expressing high levels of WT SOD1 with mutant SOD1 can accelerate disease onset and, moreover, induce disease in animals that express mutant protein at levels that are below threshold to develop ALS‐like symptoms (Deng et al. 2006, 2008; Jaarsma et al.…”

Section: Resultsmentioning

confidence: 99%

A novel variant of human superoxide dismutase 1 harboring amyotrophic lateral sclerosis‐associated and experimental mutations in metal‐binding residues and free cysteines lacks toxicity in vivo

Prudencio

Lelie

Brown

et al. 2012

Journal of Neurochemistry

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Mutations in SOD1 cause FALS. The Cu binding capacity of SOD1 has spawned hypotheses that implicate metal-mediated production of reactive species as a potential mechanism of toxicity. In past experiments, we have tested such hypotheses by mutating residues in SOD1 that normally coordinate the binding of Cu, finding that such mutants retain the capacity to induce motor neuron disease. We now describe the lack of disease in mice that express a variant of human SOD1 in which residues that coordinate the binding of Cu and Zn have been mutated (SODMD). SODMD encodes 3 disease-causing and 4 experimental mutations that ultimately eliminate all histidines involved in the binding of metals; and includes one disease-causing and one experimental mutation that eliminate secondary metal binding at C6 and C111. We show that the combined effect of these mutations produces a protein that is unstable but does not aggregate on its own, is not toxic, and does not induce disease when co-expressed with high levels of wild-type SOD1. In cell culture models, we determine that the combined mutation of C6 and C111 to G and S, respectively, dramatically reduces the aggregation propensity of SODMD and may account for the lack of toxicity for this mutant.

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“…These truncated proteins can result in diseases as a result of dominant-negative or gain-of-function mechanisms. 40 Importantly, a mutant transcript being subjected to NMD or escaping NMD can lead to distinct disease-inheritance patterns and variable clinical severity, 15,25 41 Recently, de novo truncation in the single-exon gene AHDC1 (MIM 615790) was found in subjects with a new neurological disorder, Xia-Gibbs syndrome (MIM 615829), consisting of developmental delay, hypotonia, mild dysmorphic features, sleep apnea, and other symptoms. Single-exon genes all escape NMD.…”

Section: Discussionmentioning

confidence: 99%

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome

White

Mazzeu

Hoischen

et al. 2015

The American Journal of Human Genetics

121

129

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Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.

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Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach

Cited by 7 publications

References 0 publications

FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

A novel variant of human superoxide dismutase 1 harboring amyotrophic lateral sclerosis‐associated and experimental mutations in metal‐binding residues and free cysteines lacks toxicity in vivo

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome

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