Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Ranganathan, Ramya; Haque, Shaila; Coley, Kayesha; Shepheard, Stephanie; Cooper‐Knock, Johnathan; Kirby, Janine

doi:10.3389/fnins.2020.00684

Cited by 44 publications

(33 citation statements)

References 252 publications

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“… 17 The difference reflects the contribution of rare variants captured in family studies and perhaps the relatively small numbers of cases involved in twin and pedigree studies yielding wide confidence intervals. With only 30 genes reliably identified to cause or modify ALS risk, 18 a significant proportion of heritability in ALS is still missing.…”

Section: Genetic Factorsmentioning

confidence: 99%

“…Despite this knowledge gap, the known genes are already converging on multiple functional pathways. These pathways include global protein and RNA homeostasis dysfunction, oxidative stress and inflammation, mitochondrial dysfunction, impaired cytoskeletal integrity, and altered axonal transport dynamics ( 18 , 19 ; summarized in Table 1 ). Interestingly, many of these pathways are reactive and responsive to exogenous influences.…”

Section: Genetic Factorsmentioning

confidence: 99%

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Unraveling the complex interplay between genes, environment, and climate in ALS

et al. 2022

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Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration. While the risk exerted by many environmental factors may appear small, their effect could be magnified by the presence of a genetic predisposition. We postulate that gene-environment interactions account for at least a portion of the unknown etiology in ALS. Climate underlies multiple environmental factors, some of which have been implied in ALS etiology, and the impact of global temperature increase on the gene-environment interactions should be carefully monitored. We describe the main concepts underlying such interactions. Although a lack of large cohorts with detailed genetic and environmental information hampers the search for gene-environment interactions, newer algorithms and machine learning approaches offer an opportunity to break this stalemate. Understanding how genetic and environmental factors interact to cause ALS may ultimately pave the way towards precision medicine becoming an integral part of ALS care.

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Section: Genetic Factorsmentioning

confidence: 99%

Section: Genetic Factorsmentioning

confidence: 99%

Unraveling the complex interplay between genes, environment, and climate in ALS

et al. 2022

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“…Furthermore, it was stated that different mutations in certain genes or different mutated genes can be linked to the ALS phenotype; however, the same mutation in certain genes via pleiotropy can modulate multiple phenotypic characteristics [ 20 ]. It is well established that ALS is genetically and pathologically overlapping with frontotemporal dementia (FTD), a neurodegenerative disorder whose presenting symptoms drastically differ from motor neuron diseases [ 21 ]. Finally, the effect of oligogenic inheritance was also stressed as a potential contributor to the ALS development [ 20 ].…”

Section: Phenotype Variabilitymentioning

confidence: 99%

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

Janković

Novaković

Dawod

et al. 2021

IJMS

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Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.

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“…The failure to disassemble stress granules in a controlled manner could impair the ability of cells to respond effectively to repeated stress events, and furthermore may suggest a defect in autophagy associated with DM1. Defects in autophagy have recently been implicated in several degenerative conditions (Ranganathan et al, 2020) and autophagy is known to contribute to the generation of optically transparent lens fiber cells during the differentiation of the lens epithelial stem cell population (Costello et al, 2013; Morishita et al, 2013; Morishita and Mizushima, 2016).…”

Section: Discussionmentioning

confidence: 99%

Phase-separated stress granules and processing bodies are compromised in Myotonic Dystrophy Type 1

Gulyurtlu

Magon

Guest

et al. 2021

Preprint

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RNA regulation in mammalian cells requires complex physical compartmentalisation using structures thought to be formed by liquid-liquid phase separation. Disruption of these structures is implicated in numerous degenerative diseases. Myotonic Dystrophy Type 1 (DM1) is a multi-systemic trinucleotide repeat disorder resulting from a CTG expansion in the dystonia myotonica protein kinase gene (DMPK). The cellular hall-mark of DM1 is the formation of nuclear foci containing expanded DMPK RNA (CUGexp). We report here the deregulation of stress granules and processing bodies (P-bodies), two cytoplasmic structures key for mRNA regulation, in cell culture models of DM1. Alterations to the rates of formation and dispersal of stress granules suggest an altered ability to respond to stress associated with DM1, while changes to the structure and dynamics of stress granules and P- bodies suggest that a more widespread alteration to the biophysical properties of cellular structures may be a consequence of the presence of CUGexp RNA.

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Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Cited by 44 publications

References 252 publications

Unraveling the complex interplay between genes, environment, and climate in ALS

Unraveling the complex interplay between genes, environment, and climate in ALS

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

Phase-separated stress granules and processing bodies are compromised in Myotonic Dystrophy Type 1

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