Serum Ferritin and Metal Levels as Risk Factors for Amyotrophic Lateral Sclerosis

Qureshi, Muddasir; Brown, Robert H.; Rogers, Jack T.; Cudkowicz, Merit

doi:10.2174/1874205x00802010051

Cited by 51 publications

(49 citation statements)

References 40 publications

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“…Before the discovery linking SOD1 and ALS, epidemiological studies on ALS suggested that exposure to metallic trace elements was a significant factor among many other environmental factors such as viruses, strenuous exercise, and excitotoxic chemicals that may have a role in ALS etiology (4 -6). Studies on exposure to and tissue accumulation of metallic elements in ALS patients show a correlative yet unspecified role for many metals including copper and zinc in SOD1-related ALS (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Over the years, a number of hypotheses relating metal toxicity to ALS have been proposed.…”

mentioning

confidence: 99%

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Lelie

Liba

Bourassa

et al. 2011

Journal of Biological Chemistry

120

138

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Mutations in the metalloenzyme copper-zinc superoxide dismutase (SOD1) cause one form of familial amyotrophic lateral sclerosis (ALS), and metals are suspected to play a pivotal role in ALS pathology. To learn more about metals in ALS, we determined the metallation states of human wild-type or mutant (G37R, G93A, and H46R/H48Q) SOD1 proteins from SOD1-ALS transgenic mice spinal cords. SOD1 was gently extracted from spinal cord and separated into insoluble (aggregated) and soluble (supernatant) fractions, and then metallation states were determined by HPLC inductively coupled plasma MS. Insoluble SOD1-rich fractions were not enriched in copper and zinc. However, the soluble mutant and WT SOD1s were highly metallated except for the metal-bindingregion mutant H46R/H48Q, which did not bind any copper. Due to the stability conferred by high metallation of G37R and G93A, it is unlikely that these soluble SOD1s are prone to aggregation in vivo, supporting the hypothesis that immature nascent SOD1 is the substrate for aggregation. We also investigated the effect of SOD1 overexpression and disease on metal homeostasis in spinal cord cross-sections of SOD1-ALS mice using synchrotron-based x-ray fluorescence microscopy. In each mouse genotype, except for the H46R/H48Q mouse, we found a redistribution of copper between gray and white matters correlated to areas of high SOD1. Interestingly, a diseasespecific increase of zinc was observed in the white matter for all mutant SOD1 mice. Together these data provide a picture of copper and zinc in the cell as well as highlight the importance of these metals in understanding SOD1-ALS pathology.First described in 1869 by French neurologist Jean-Martin Charcot (1), amyotrophic lateral sclerosis (ALS) 4 is defined by the progressive demise of lower and upper motor neurons leading to the degeneration of muscle tissue and eventual paralysis (2). Familial ALS was linked in 1993 to mutations in the gene that encodes the metalloenzyme copper-zinc, superoxide dismutase (SOD1) (3), and since that time more than 140 different disease-causing mutations have been identified (4). Before the discovery linking SOD1 and ALS, epidemiological studies on ALS suggested that exposure to metallic trace elements was a significant factor among many other environmental factors such as viruses, strenuous exercise, and excitotoxic chemicals that may have a role in ALS etiology (4 -6). Studies on exposure to and tissue accumulation of metallic elements in ALS patients show a correlative yet unspecified role for many metals including copper and zinc in SOD1-related ALS (7-19). Over the years, a number of hypotheses relating metal toxicity to ALS have been proposed. For example, abnormal accumulations of redox-active metal ions such as iron or copper in ALS patients were generally believed to be detrimental due to their ability to mediate oxidative damage through participation in reactions that lead to formation of reactive oxygen species. A more specific hypothesis linking metallation levels of mutant SOD1 to...

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mentioning

confidence: 99%

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Lelie

Liba

Bourassa

et al. 2011

Journal of Biological Chemistry

120

138

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“…Specifically, injection of Al-containing adjuvants at levels comparable to those that are administered to human adults resulted in the death of motor neurons, impairments in motor function, decrements in spatial memory capacity in young mice and significant increases in activated astrocytes and microglia (Petrik et al, 2007;Shaw and Petrik, 2009). Blood and urine levels of Al may also be elevated in ALS (Perl et al, 1982) but there is disagreement concerning this (Qureshi et al, 2008).…”

Section: Link Between Aluminum Exposure and Neurodegenerative Conditimentioning

confidence: 99%

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

Bondy

2016

NeuroToxicology

208

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“…38 Metal toksisitesinin ALS ve diğer nörodejeneratif hastalıklarda risk faktörü olduğu düşünülse de 321 hastanın değerlendirildiği retrospektif bir çalışmada, idrar Al düzeylerinin normal sınırlar içinde olduğu bildirilmiştir. 39 ALS tanısı olan beş hastanın ventral servikal spinal kord örnekleri alınarak Al, Ca ve Fe düzeyleri ölçüldüğünde, Al düzeylerinin kontrole göre fark göstermediği, sadece Fe düzeylerin yük-sek olduğu saptanmıştır. 40 Benzer şekilde 100 ALS ve 100 sağlıklı kontrolde yapılan saç analizlerinde, vanadyum, Al, Mg ve Mn düzeylerinde anlamlı bir fark görülmemiştir.…”

Section: Amyotrofi̇k Lateral Sklerozunclassified

Aluminum Toxicity and its Role in Neurodegenerative Diseases: Review

Sipahi¹,

Palabıyık²,

Balci³

et al. 2015

Turkiye Klinikleri J Neur

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6Alüminyum Toksisitesi ve Nörodejeneratif Hastalıklardaki Rolü Ö ÖZ ZE ET T Günlük yaşamımızda çok yaygın kullanılan alüminyum (Al), oksijen ve silikondan sonra yeryüzünde en fazla bulunan üçüncü elementtir. Endüstride paketleme, inşaat, elektrik aletleri ve içecek kutuları gibi birçok farklı ürünün yapımında kullanılan Al bileşikleri gıda katkı maddesi olarak da kullanılmaktadır. Türkiye'de de Gıda, Tarım ve Hayvancılık Bakanlığı tarafından "Türk Gıda Kodeksi Gıda Katkı Maddeleri Yönetmeliği" ekinde gıda katkı maddesi olarak kullanımına izin verilen miktarlar belirtilmiştir. Al gıdalara özellikle ilave edildiği durumlar dışında, kontaminasyon olarak da bulunmaktadır. Ayrıca gıdaların paketlenmesinde Al folyo kullanılması, gıdaların yüksek ısıda Al folyoda pişirilmesi de gıdaların Al içeriğini arttırmaktadır. Ancak gıda zincirindeki Al miktarı, antiasitler ve analjezikler gibi ilaçlarda kullanılan miktarıyla kıyaslandığında oldukça azdır. Al toksisitesi çoğunlukla kronik renal hasarı olan hastalarda veya iş yerinde Al'a maruz kalanlarda gö-rülmektedir. Akciğer, kemik ve santral sinir sistemi ana hedef organlardır. Alzheimer hastalığı, Parkinson hastalığı, Huntington hastalığı, Amyotrofik lateral skleroz, spinal muskuler atrofi gibi dünyada milyonlarca insanı etkileyen ve henüz kesin bir çözüm bulunamayan nörodejeneratif hastalıklarda beyin nöronlarının oksidatif strese oldukça duyarlı olduğu ve bunun Al toksisitesiyle indüklenebi-leceği düşünülmektedir. Deney hayvanlarında yapılan çalışmalar Al'un nörotoksik olduğunu, kanbeyin bariyerinin geçirgenliğini arttırdığını ve beyinde pek çok önemli enzimi inhibe ettiğini göstermiştir. Demansın belirgin olarak gözlenmediği diyaliz hastalarında da kan Al konsantrasyonları oldukça yüksek bulunmuştur. Ayrıca Al başta olmak üzere bazı toksik metaller düzeylerinde otistik çocuklarda sağlıklı çocuklara göre artış gözlenmiştir. Bu derlemenin amacı, yaygın kullanım alanına sahip Al'un nörodejeneratif hastalıklardaki rolünü değerlendirmektir.

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Serum Ferritin and Metal Levels as Risk Factors for Amyotrophic Lateral Sclerosis

Cited by 51 publications

References 40 publications

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

Aluminum Toxicity and its Role in Neurodegenerative Diseases: Review

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