Genetic epidemiology of amyotrophic lateral sclerosis

Majoor‐Krakauer, Danielle; Willems, Patrick J.; Hofman, Albert

doi:10.1046/j.0009-9163.2002.00001.x

Cited by 126 publications

(92 citation statements)

References 265 publications

(311 reference statements)

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“…Familial ALS (FALS) is observed in approximately 10% of all cases, but substantially more ALS cases are suspected to be influenced by genetic factors (72). In addition to the variants in MAPT (see above), mutations in 2 genes (SOD1 and ALS2; Table 1) have been shown to cause FALS.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

The genetic epidemiology of neurodegenerative disease

Bertram

Tanzi²

2005

Journal of Clinical Investigation

560

345

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Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.

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Section: Frontotemporal Dementiamentioning

confidence: 99%

The genetic epidemiology of neurodegenerative disease

Bertram

Tanzi²

2005

Journal of Clinical Investigation

560

345

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“…Although ALS is predominately a sporadic disease, ϳ10% of cases are inherited in an autosomal dominant manner and a subset of these fALS cases are caused by mutations in the SOD1 gene (1). The gene product of SOD1, cytoplasmic Cu,Zn-superoxide dismutase (SOD1), is a ubiquitously expressed enzyme that catalyzes the disproportionation reaction of superoxide radicals (1).…”

Section: Alsmentioning

confidence: 99%

Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis

Rakhit

Crow

Lepock

et al. 2004

Journal of Biological Chemistry

304

303

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Proteinacious intracellular aggregates in motor neurons are a key feature of both sporadic and familial amyotrophic lateral sclerosis (ALS). These inclusion bodies are often immunoreactive for Cu,Zn-superoxide dismutase (SOD1) and are implicated in the pathology of ALS. On the basis of this and a similar clinical presentation of symptoms in the familial (fALS) and sporadic forms of ALS, we sought to investigate the possibility that there exists a common disease-related aggregation pathway for fALS-associated mutant SODs and wild type SOD1. We have previously shown that oxidation of fALS-associated mutant SODs produces aggregates that have the same morphological, structural, and tinctorial features as those found in SOD1 inclusion bodies in ALS. Here, we show that oxidative damage of wild type SOD at physiological concentrations (ϳ40 M) results in destabilization and aggregation in vitro. Oxidation of either mutant or wild type SOD1 causes the enzyme to dissociate to monomers prior to aggregation. Only small changes in secondary and tertiary structure are associated with monomer formation. These results indicate a common aggregation prone monomeric intermediate for wild type and fALS-associated mutant SODs and provides a link between sporadic and familial ALS. ALS1 is a fatal neurodegenerative disease that leads to the selective loss of motor neurons. Although ALS is predominately a sporadic disease, ϳ10% of cases are inherited in an autosomal dominant manner and a subset of these fALS cases are caused by mutations in the SOD1 gene (1). The gene product of SOD1, cytoplasmic Cu,Zn-superoxide dismutase (SOD1), is a ubiquitously expressed enzyme that catalyzes the disproportionation reaction of superoxide radicals (1). There are several lines of evidence that SOD1 mutations result in a gain, rather than loss of function that causes ALS. For instance, some fALS-associated mutant SOD1s retain full enzymatic activity (2). In addition, SOD1 knock-out mice lack ALS symptoms, whereas transgenic mice expressing the fALS-associated mutant G93A SOD1 develop ALS-like symptoms despite expression of endogenous mouse SOD1 (3). Lastly, overexpression of human wild type SOD1 fails to alleviate symptoms in this transgenic mouse model for ALS (3). One hypothesis of the gain of function of SOD1 is that misfolding of the mutant alters the catalytic mechanism to allow production of oxidants such as peroxynitrite (4) and possibly hydrogen peroxide (5). These reactive nitrogen and oxygen species cause toxicity by accumulated damage to proteins, nucleic acids, and lipids. Another major hypothesis is toxicity caused by intracellular aggregation of SOD1. SOD1 inclusion bodies, which also react with anti-ubiquitin antibodies, are a common pathological finding in motor neurons and neighboring astrocytes of ALS patients (6). These two hypotheses, however, are not mutually exclusive when considering that oxidative modification of proteins may contribute to aggregation and protease resistance. Protein aggregates are a common pathological feature...

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“…Ten percent of the ALS patients are congenital cases called familial ALS (FALS) which is caused by mutations of the Cu,Zn-superoxide dismutase (Cu,Zn-SOD) gene [Majoor-Krakauer et al, 2003]. The other 90% of ALS cases which have unknown causes are called sporadic ALS (SALS).…”

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confidence: 99%

Effects of cadmium on structure and enzymatic activity of Cu,Zn‐SOD and oxidative status in neural cells

Huang

Shih

Huang

et al. 2006

J of Cellular Biochemistry

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder disease. Ten percent of the ALS patients are congenital (familial ALS), and the other 90% are sporadic ALS (SALS). It has been shown that mutations found in the Cu,Zn-SOD cause 20% of the familial ALS due to its low enzyme activity. We hypothesized that heavy metals may interfere the structure of Cu,Zn-SOD protein to suppress its activity in some of the SALS. In this study, we expressed and characterized the recombinant human Cu,Zn-SOD under various concentrations of Cu . By atomic absorption spectrophotometry, we demonstrated that adding of cadmium significantly increased the content of cadmium ion, but reduced its Zn 2þ content and enzyme activity of the Cu,Zn-SOD protein. The data of circular dichroism spectra demonstrated that the secondary structure of Cu,Zn-SOD/Cd is different from Cu,Zn-SOD, but close to apo-SOD. In addition to the effect of cadmium on Cu,Zn-SOD, cadmium was also shown to induce neural cell apoptosis. To further investigate the mechanism of neural cell apoptosis induced by cadmium, we used proteomics to analyze the altered protein expressions in neural cells treated with cadmium. The altered proteins include cellular structural proteins, stressrelated and chaperone proteins, proteins involved in reactive oxygen species (ROS), enzyme proteins, and proteins that mediated cell death and survival signaling. Taken together, in this paper, we demonstrate that cadmium decreases the content of Zn 2þ , changes the conformation of Cu,Zn-SOD protein to decrease its enzyme activity, and causes oxidative stress-induced neural cell apoptosis.

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Genetic epidemiology of amyotrophic lateral sclerosis

Cited by 126 publications

References 265 publications

The genetic epidemiology of neurodegenerative disease

The genetic epidemiology of neurodegenerative disease

Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis

Effects of cadmium on structure and enzymatic activity of Cu,Zn‐SOD and oxidative status in neural cells

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