The contribution of mitochondrial dysfunction to a gene–environment model of Guamanian ALS and PD

Lynch, Daniel; Wanglund, Christian; Spathis, Rita; Chan, Chim W.; Reiff, Dana M.; Lum, J. Koji; Garruto, Ralph M.

doi:10.1016/j.mito.2007.09.002

Cited by 18 publications

(16 citation statements)

References 44 publications

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“…Moreover, BMAA-treated TH-positive cells showed an increased ROS production, prevented by the antioxidant DTT, and a release of cyt-c from mitochondria. In this regard, it has been reported a higher frequency of somatic mutations in mitochondrial genome in Guam ALS and PD patients than in Guam controls, suggesting that mitochondria dysfunction may contribute, as genetic susceptibility, to ALS-PDC disease (Lynch et al, 2008). Interestingly, application of the potent mGluR1 antagonist JNJ 16259685 considerably reduced cyt-c release, suggesting that mGluR1 are the principal mediators of the BMAA-induced mitochondrial stress.…”

Section: Discussionmentioning

confidence: 98%

Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons

et al. 2010

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Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, andAlzheimer's symptoms that is prevalent in the Guam population. ␤-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration (

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Section: Discussionmentioning

confidence: 98%

Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons

et al. 2010

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“…Lynch et al (32) recently proposed a novel gene/environment interaction model in which the combined effects of eight risk factors for ALS-G/PD-G (among them TRPM7 T1482I and mitochondrial DNA mutations) provided a statistically significant predisposition to these disorders. It would be interesting to include TRPM2 P1018L in that analysis.…”

Section: Discussionmentioning

confidence: 99%

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

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et al. 2008

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

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Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca 2؉ and Mg 2؉ , coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calciumpermeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2 P1018L , produces a missense change in the channel protein whereby proline 1018 (Pro 1018 ) is replaced by leucine (Leu 1018 ). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.calcium ͉ neurodegeneration ͉ oxidative stress ͉ channelopathy ͉ gene environment

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“…Throughout Melanesia, haplogroup B lineages are found predominantly in coastal regions and offshore islands associated with prehistoric Lapita settlements and the current distribution of Austronesian languages (Merriwether et al 1999). Haplogroup B approaches fixation throughout Polynesia, as well as on the central-eastern Micronesian islands derived from the expansion of the Lapita Cultural Complex (Lum et al 1994;Sykes et al 1995;Cann 1998, 2000), with variable frequencies observed in western Micronesia Cann 1998, 2000;Lynch et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Reconstructing the origin of the Lapita Cultural Complex: mtDNA analyses of East Sepik Province, PNG

et al. 2008

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The colonization of Oceania occurred in two waves. By 32,000 BP, humans had reached New Guinea and settled all intervisible islands east to the Solomon Islands. Around 3,500 BP, a distinct intrusive group from Southeast Asia reached coastal New Guinea, integrated their components with indigenous resources, and gave rise to the Lapita Cultural Complex. Within 2,500 years, Lapita and its descendant cultures colonized the Pacific. To uncover the origin of the Lapita Cultural Complex, we analyzed the hypervariable region I of the mitochondrial deoxyribonucleic acid (mtDNA) in 219 individuals from eight East Sepik Province villages: two villages in each of four environmental zones. Same-zone villages spoke different languages: one Austronesian and three Papuan (Arapesh, Abelam, and Boiken). Our analysis examined whether language or geography better predicted gene flow. In general, language better predicted genetic affinities. Boiken villages across all four zones showed no significant genetic difference (F ST P value [ 0.05). In contrast, the Austronesian village was significantly different to most other villages (P \ 0.05). Only the mountains and coast showed zonal gene flow (P [ 0.05). We interpret the data to reflect limited gene flow inland by Austronesians overshadowed by a regional displacement by inland Boiken speakers migrating seaward. These results are consistent with oral histories and ethnographic accounts.

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The contribution of mitochondrial dysfunction to a gene–environment model of Guamanian ALS and PD

Cited by 18 publications

References 44 publications

Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons

Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

Reconstructing the origin of the Lapita Cultural Complex: mtDNA analyses of East Sepik Province, PNG

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