Disappearance of high‐incidence amyotrophic lateral sclerosis and parkinsonism‐dementia on Guam

Garruto, Ralph M.; Yanagihara, R; Gajdusek, D. Carleton

doi:10.1212/wnl.35.2.193

Cited by 204 publications

(84 citation statements)

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“…Mg 2ϩ in the water supply is similarly low, about 10-fold lower in the South. This hypothesis also helps explain the observed decline of ALS-G and PD-G in recent years in parallel with modernization (6,30) with the accompanying changes in diet as well as the establishment of a treated water supply system. A check of the SNP database reveals that the T1482I variant of 1403-1864).…”

Section: Resultsmentioning

confidence: 84%

A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders

Hermosura

Nayakanti

Dorovkov

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

188

151

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Guamanian amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia (PD-G) have been epidemiologically linked to an environment severely deficient in calcium (Ca 2؉ ) and magnesium (Mg 2؉ ). Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein containing both channel and kinase domains that has been proposed to be involved in the homeostatic regulation of intracellular Ca 2؉ , Mg 2؉ , and trace metal ion concentration. There is evidence that TRPM7 is constitutively active and that the number of available channels is dependent on intracellular free Mg 2؉ levels. We found a TRPM7 variant in a subset of ALS-G and PD-G patients that produces a protein with a missense mutation, T1482I. Recombinant T1482I TRPM7 exhibits the same kinase catalytic activity as WT TRPM7. However, heterologously expressed T1482I TRPM7 produces functional channels that show an increased sensitivity to inhibition by intracellular Mg 2؉ . Because the incidence of ALS-G and PD-G has been associated with prolonged exposure to an environment severely deficient in Ca 2؉ and Mg 2؉ , we propose that this variant TRPM7 allele confers a susceptibility genotype in such an environment. This study represents an initial attempt to address the important issue of gene-environment interactions in the etiology of these diseases.amyotrophic lateral sclerosis ͉ calcium ͉ gene-environment interactions ͉ phosphorylation ͉ parkinsonism dementia

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Section: Resultsmentioning

confidence: 84%

A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders

Hermosura

Nayakanti

Dorovkov

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

188

151

View full text Add to dashboard Cite

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“…The average annual incidence of PDC per 100,000 for the period 1960-1979 declined from 55 to 25 for men, but only from 23 to 21 for women. In 1985, Garruto et al [29] reported a similar magnitude of decline in the age-adjusted incidence rates for men and women. Results of a 15-year follow-up study in 1983 of a random sample of adult Chamorros from all villages on Guam reported conflicting findings.…”

Section: Pathologymentioning

confidence: 89%

Neuroepidemiologic Research Initiatives on Guam: Past and Present

Wiederholt

1999

Neuroepidemiology

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Since the middle of this century, a remarkable concentration of cases of neurodegenerative disease(s), referred to as amyotrophic lateral sclerosis and Parkinson-dementia complex (ALS/PDC), has been recognized among Chamorro natives of Guam. Intense investigations over the last 4 decades have failed to determine the etiology of these invariably fatal diseases. Over the same time period, the incidence of ALS has decreased dramatically, the incidence of PDC has decreased, but to a lesser degree, and age at onset has shifted to a later age by about 1 decade. Almost 50% of demented patients present without the classical Parkinsonian features of PDC, and the morphological picture has changed. Results of past and present research initiatives are reviewed.

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“…The disorder is found together with a second high-incidence disease, amyotrophic lateral sclerosis (ALS). The incidence of both diseases has declined dramatically over the past half century, suggesting an environmental etiology (1). The neuropathology of PD is hallmarked by neurofibrillary tangles (NFTs) (2) of paired helical filaments (PHFs) composed of abnormally hyperphosphorylated forms of the microtubule-associated protein tau.…”

mentioning

confidence: 99%

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

Arif

Kazim

Grundke‐Iqbal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. β-N-methylamino-Lalanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr 307 and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr 307 in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAAinduced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr 307 . These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr 307 by Src.Alzheimer's disease | amyotrophic lateral sclerosis | tauopathies | tau phosphorylation | cycad

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Disappearance of high‐incidence amyotrophic lateral sclerosis and parkinsonism‐dementia on Guam

Cited by 204 publications

References 0 publications

A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders

A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders

Neuroepidemiologic Research Initiatives on Guam: Past and Present

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

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