Amyotrophic Lateral Sclerosis in a Battery-factory Worker Exposed to Cadmium

Bar-Sela, S; Reingold, S. M.; Richter, Elihu D.

doi:10.1179/107735201800339470

Cited by 51 publications

(42 citation statements)

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“…Metals have been studied for a long time in order to understand pathogenic mechanisms underlying development of neurodegenerative disease better, and to date there are prospects of study for this topic [71]. As for cadmium, apart from recent evidence of a high metal concentration in the cerebrospinal fluid of ALS patients [85], there are some works focusing on occupational exposures in certain employment sectors, such as production of nickel-cadmium batteries [86,87]. Some evidence in experimental models concerning neurotoxicity of other metals such as zinc and copper [88,89] is also present in scientific literature, but there is no strong evidence concerning relationship with ALS.…”

Section: Discussionmentioning

confidence: 99%

Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus

Garzillo

Miraglia

Pedata

et al. 2015

Int J Occup Med Environ Health

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons. In recent years, in addition to several studies about genetic mechanisms leading to motor neurons damage, various epigenetic theories have been developed, involving the study of the patients' work and lifestyle. The work aims at focusing the role of occupational exposure related to ALS by literature data analysis. Articles, selected on the basis of keywords, year of publication and topics, are related to occupational exposure, suggesting an impact on ALS onset. The literature review shows that there are still a lot of biases in the studies design, which actually do not allow to draw unequivocal conclusions.

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Section: Discussionmentioning

confidence: 99%

Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus

Garzillo

Miraglia

Pedata

et al. 2015

Int J Occup Med Environ Health

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“…In humans, Cd 2+ concentrations are significantly elevated in the brains of AD (Lui et al, 1990) and ALS (Vinceti et al, 1997) patients. Also, occupational exposure to Cd 2+ increases the risk of AD (Bar-Sela et al, 2001), ALS, and brain atrophy (Bar-Sela et al, 1992). Exposure to Cd 2+ can cause the development of parkinsonism three months after recovery from acute Cd 2+ toxicity (Okuda et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

Song

Xiao

Nagashima

et al. 2008

Toxicology and Applied Pharmacology

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Cadmium (Cd 2+ ) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd 2+ is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded proteins in the lesions. Here, we report that Cd 2+ directly induces the formation of protein inclusion bodies in cells. The protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd 2+ -treated cell lysates. Proteomic analysis identified 145 proteins in the aggresome-enriched fractions. One of the proteins is the highly conserved valosin-containing protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated proteins through its N domain (#1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd 2+ indicate that the C-terminal tail (#780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated proteins or HDAC6. Our results indicate that Cd 2+ induces the formation of protein inclusion bodies by promoting the accumulation of ubiquitinated proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated proteins has important implications for understanding Cd 2+ toxicity and associated diseases.

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“…Cadmium is known as a potent toxic metal in industrial and food contamination, and it is harmful to human because it accumulates in liver, kidney, and other tissues. It has been reported that cadmium exposure causes ALS by reducing the superoxide dismutase activity [Bar-sela et al, 2001]. However, the mechanism of cadmium decrease the activity of Cu,Zn-SOD protein is not clear.…”

mentioning

confidence: 98%

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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Amyotrophic Lateral Sclerosis in a Battery-factory Worker Exposed to Cadmium

Cited by 51 publications

References 0 publications

Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus

Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

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

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