Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

Bradley, Walter G.; Andrew, Angeline S.; Traynor, Bryan J.; Chiò, Adriano; Butt, Tanya; Stommel, Elijah W.

doi:10.1159/000495321

Cited by 35 publications

(19 citation statements)

References 30 publications

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“…However, subjects that have been considered non-exposed ALS patients may have been exposed to one or more other factors that are able to alter similar genetic pathways, thereby guiding the ALS phenotype. This is in line with Bradley et al ( 80 ) who hypothesized that “there are many combinations of individual, specific, genetic, and environmental factors, and that each combination can lead to the development of the syndrome of ALS” through complex gene-environment interactions ( 80 – 82 ).…”

Section: Running Hypotheses and Key Molecular Interactivity In Als Desupporting

confidence: 86%

Destination Amyotrophic Lateral Sclerosis

Keon¹,

Musrie²,

Dinger

et al. 2021

Front. Neurol.

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Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons both in the brain and spinal cord. The constantly evolving nature of ALS represents a fundamental dimension of individual differences that underlie this disorder, yet it involves multiple levels of functional entities that alternate in different directions and finally converge functionally to define ALS disease progression. ALS may start from a single entity and gradually becomes multifactorial. However, the functional convergence of these diverse entities in eventually defining ALS progression is poorly understood. Various hypotheses have been proposed without any consensus between the for-and-against schools of thought. The present review aims to capture explanatory hierarchy both in terms of hypotheses and mechanisms to provide better insights on how they functionally connect. We can then integrate them within a common functional frame of reference for a better understanding of ALS and defining future treatments and possible therapeutic strategies. Here, we provide a philosophical understanding of how early leads are crucial to understanding the endpoints in ALS, because invariably, all early symptomatic leads are underpinned by neurodegeneration at the cellular, molecular and genomic levels. Consolidation of these ideas could be applied to other neurodegenerative diseases (NDs) and guide further critical thinking to unveil their roadmap of destination ALS.

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Section: Running Hypotheses and Key Molecular Interactivity In Als Desupporting

confidence: 86%

Destination Amyotrophic Lateral Sclerosis

Keon¹,

Musrie²,

Dinger

et al. 2021

Front. Neurol.

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“…ALS is a complex disease, and this complexity is mostly due to the heterogeneity of its phenotype, influenced by genetics through oligogenic mechanisms, that is, through gene-gene (or protein-protein) interactions [12,19] and by demographic factors, including age and sex, and by environment, which have longstanding negative effects, probably interacting with genetics through epigenetic mechanisms (i.e., interactomics) [38,47,110]. It is important that this complex scenario is taken into account when exploring the multiple disease pathways involved in ALS and when approaching therapy development.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Trojsi

D’Alvano

Bonavita

et al. 2020

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

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“…Frontal temporal dementia, Parkinson's disease, Alzheimer's disease, and ALS are all likely related and environmental exposures can potentially lead to a variety of neurodegenerative processes. As we learn more about risk factors for ALS and the pattern of accumulation of those risk factors, we realize that BMAA is only one of the causative factors for ALS (Chiò et al 2018;Bradley et al 2019). If one considers that ALS may be related to a series of environmental triggers, one of them being BMAA, this pallet of toxins is likely different in Guam than in the rest of the world.…”

Section: Als/pdc Is a Neurodegenerative Disease With Similarities Tomentioning

confidence: 99%

“…The mechanisms of neurodegenerative diseases are only partially understood and while growing evidence demonstrates that exposure to BMAA may increase the risk of disease, understanding of the degree of exposure that constitutes risk is currently nascent and requires further investigation. Geneenvironment interactions may influence the development of the clinical-pathological phenotype expressed as a specific form of neurodegenerative disease in some individuals, but not others (Bradley et al 2019). While a direct link has been demonstrated between the ingestion of BMAA and the onset of Guamanian ALS/PDC neuropathology in non-human primates (Cox et al 2016;Banack and Cox 2018;Davis et al 2020), the same causative link has not yet been proven between BMAA and progressive neurodegenerative disease outside of Guam.…”

Section: Bmaa In Ad and Als Brainsmentioning

confidence: 99%

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Is Exposure to BMAA a Risk Factor for Neurodegenerative Diseases? A Response to a Critical Review of the BMAA Hypothesis

Dunlop

et al. 2021

Neurotox Res

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In a literature survey, Chernoff et al. (2017) dismissed the hypothesis that chronic exposure to β-N-methylamino-L-alanine (BMAA) may be a risk factor for progressive neurodegenerative disease. They question the growing scientific literature that suggests the following: (1) BMAA exposure causes ALS/PDC among the indigenous Chamorro people of Guam; (2) Guamanian ALS/PDC shares clinical and neuropathological features with Alzheimer’s disease, Parkinson’s disease, and ALS; (3) one possible mechanism for protein misfolds is misincorporation of BMAA into proteins as a substitute for L-serine; and (4) chronic exposure to BMAA through diet or environmental exposures to cyanobacterial blooms can cause neurodegenerative disease. We here identify multiple errors in their critique including the following: (1) their review selectively cites the published literature; (2) the authors reported favorably on HILIC methods of BMAA detection while the literature shows significant matrix effects and peak coelution in HILIC that may prevent detection and quantification of BMAA in cyanobacteria; (3) the authors build alternative arguments to the BMAA hypothesis, rather than explain the published literature which, to date, has been unable to refute the BMAA hypothesis; and (4) the authors erroneously attribute methods to incorrect studies, indicative of a failure to carefully consider all relevant publications. The lack of attention to BMAA research begins with the review’s title which incorrectly refers to BMAA as a “non-essential” amino acid. Research regarding chronic exposure to BMAA as a cause of human neurodegenerative diseases is emerging and requires additional resources, validation, and research. Here, we propose strategies for improvement in the execution and reporting of analytical methods and the need for additional and well-executed inter-lab comparisons for BMAA quantitation. We emphasize the need for optimization and validation of analytical methods to ensure that they are fit-for-purpose. Although there remain gaps in the literature, an increasingly large body of data from multiple independent labs using orthogonal methods provides increasing evidence that chronic exposure to BMAA may be a risk factor for neurological illness.

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Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

Cited by 35 publications

References 30 publications

Destination Amyotrophic Lateral Sclerosis

Destination Amyotrophic Lateral Sclerosis

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Is Exposure to BMAA a Risk Factor for Neurodegenerative Diseases? A Response to a Critical Review of the BMAA Hypothesis

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