Search for a red cell enzyme or serum protein marker in amyotrophic lateral sclerosis and parkinsonism‐dementia of guam

Blake, N. M.; Kirk, R. L.; Wilson, Susan R.; Garruto, Ralph M.; Gajdusek, D. Carleton; Gibbs, Clarence J.; Hoffman, Paul M.; Opitz, John M.

doi:10.1002/ajmg.1320140210

“…The Al/DNA-P ratio of whole, normal, human neuron cell nuclei (not only the heterochromatin) was, according to the quoted investigation, 700 ,ug/g DNA-equivalent to an Al/DNA-P molar ratio of 0.008 (106). A simple calculation shows that this must be a high ratio.…”

Section: Lymphocytesmentioning

confidence: 92%

Metabolism and possible health effects of aluminum.

Ganrot¹

1986

Environ Health Perspect

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Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind.

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“…Originally, it was believed that this disease is an autosomal dominant disorder with complete penetrance in males and ~50% penetrance in females [65]. However, as no marker system associated with this disorder was found, it has been concluded that "local environmental factors are most likely involved in pathogenesis" [68,69]. This hypothesis was supported by the fact that the high incidence of ALS/PD in Guam disappeared when isolation was disrupted and travel and economic changes brought food and water sources from the outside.…”

Section: -Synuclein In Dlb and Other Lewy Body Disordersmentioning

confidence: 98%

α-Synuclein Misfolding and Neurodegenerative Diseases

Uversky

¹

2008

CPPS

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Alpha-synuclein is an abundant presynaptic brain protein, misfolding, aggregation and fibrillation of which are implicated as critical factors in several neurodegenerative diseases. The list of the well-known synucleinopathies includes such devastating disorders as Parkinson's disease, Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, dementia with Lewy bodies, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. The precise functions of alpha-synuclein remain elusive, but there are evidence indicating its involvement in regulation vesicular release and/or turnover and synaptic function in the central nervous system. It might play a role in neuronal plasticity responses, bind fatty acids, regulate certain enzymes, transporters, and neurotransmitter vesicles, be involved in neuronal survival and even can act as a molecular chaperone. Structurally, alpha-synuclein is an illustrative member of the rapidly growing family of natively unfolded (or intrinsically disordered) proteins and considerable knowledge has been accumulated about its structural properties and conformational behavior. The molecular mechanisms underlying misfolding, aggregation and fibrillation of alpha-synuclein and the role of various environmental and genetic factors in stimulation and inhibition of these processes are relatively well understood. Here, the main structural features of alpha-synuclein, its functions, and involvement in various human diseases are summarized providing a foundation for better understanding of the biochemistry, biophysics and neuropathology of alpha-synuclein aggregation.

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“…Epidemiological studies mostly support an environmental factor, connected to the traditional life pattern, as a probable cause of the disease. A higher incidence was observed on Guam than on the other nearby islands and it was greatest in some ofthe most southern villages, reported to be least westernized (682,699,700).…”

Section: Diseases With Proposed Al3" Connectionmentioning

confidence: 84%

Metabolism and Possible Health Effects of Aluminum

Ganrot¹

1986

Environmental Health Perspectives

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Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind.

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Search for a red cell enzyme or serum protein marker in amyotrophic lateral sclerosis and parkinsonism‐dementia of guam

Cited by 15 publications

References 16 publications

Metabolism and possible health effects of aluminum.

Metabolism and possible health effects of aluminum.

α-Synuclein Misfolding and Neurodegenerative Diseases

Metabolism and Possible Health Effects of Aluminum

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Search for a red cell enzyme or serum protein marker in amyotrophic lateral sclerosis and parkinsonism‐dementia of guam

Cited by 15 publications

References 16 publications

Metabolism and possible health effects of aluminum.

Metabolism and possible health effects of aluminum.

&#945;-Synuclein Misfolding and Neurodegenerative Diseases

Metabolism and Possible Health Effects of Aluminum

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α-Synuclein Misfolding and Neurodegenerative Diseases