Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Zhang, Sai; Cooper‐Knock, Johnathan; Weimer, Annika K.; Shi, Minyi; Moll, Tobias; Marshall, Jack N G; Harvey, Calum; Nezhad, Helia Ghahremani; Franklin, John; Souza, Catiane; Ning, Ke; Wang, Cheng; Li, Jingjing; Dilliott, Allison A.; Farhan, Sali M.K.; Elhaik, Eran; Pasniceanu, Iris-Stefania; Livesey, Matthew R.; Eitan, Chen; Hornstein, Eran; Kenna, Kevin P.; Veldink, Jan H.; Ferraiuolo, Laura; Shaw, Pamela J.; Snyder, M

doi:10.1016/j.neuron.2021.12.019

Cited by 81 publications

(49 citation statements)

References 133 publications

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“…Cytoskeleton and FA convert intracellular and extracellular mechanical forces into intracellular signals that induce mechanical stress responses ( Hurtley, 1998 ; Fletcher and Mullins, 2010 ; López-Colomé et al, 2017 ). The cytoskeletal dysfunction was found as a feature of neurodegenerative diseases, for example Parkinson’s disease ( McLean et al, 2000 ; Sweers et al, 2011 ; Häbig et al, 2013 ; Lu et al, 2017 ), Alzheimer’s disease ( Bamburg and Bloom, 2009 ; Levy Nogueira et al, 2016 ), and ALS ( Wu et al, 2012 ; Smith et al, 2014 ; Nicolas et al, 2018 ; Zhang et al, 2022 ). However, it is unclear whether the mechanical stress response is associated with the pathogenesis of neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response

Shiota

Nagata

Kikuchi

et al. 2022

Front. Cell Dev. Biol.

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Proline:arginine (PR) poly-dipeptides from the GGGGCC repeat expansion in C9orf72 have cytotoxicity and bind intermediate filaments (IFs). However, it remains unknown how PR poly-dipeptides affect cytoskeletal organization and focal adhesion (FA) formation. Here, we show that changes to the cytoskeleton and FA by PR poly-dipeptides result in the alteration of cell stiffness and mechanical stress response. PR poly-dipeptides increased the junctions and branches of the IF network and increased cell stiffness. They also changed the distribution of actin filaments and increased the size of FA and intracellular calcium concentration. PR poly-dipeptides or an inhibitor of IF organization prevented cell detachment. Furthermore, PR poly-dipeptides induced upregulation of mechanical stress response factors and led to a maladaptive response to cyclic stretch. These results suggest that the effects of PR poly-dipeptides on mechanical properties and mechanical stress response may serve as a pathogenesis of C9orf72-related neurodegeneration.

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Section: Introductionmentioning

confidence: 99%

C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response

Shiota

Nagata

Kikuchi

et al. 2022

Front. Cell Dev. Biol.

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“…Project MinE is at the forefront of these approaches, with efforts to sequence the genome and connect findings with transcriptome, epigenome, and noncoding genome findings. 55 , 56 Other data sets are also taking integrative approaches and providing resources for researchers at large for straightforward access to sample data. The Answer ALS consortium is one such approach, which provides whole genome data along with induced pluripotent stem cell lines and their corresponding transcriptome data, thereby saving researchers precious time and resources in trying to generate their own version of these lines.…”

Section: Challenges In Als Genetics and Exploring Emerging Solutionsmentioning

confidence: 99%

Progress in Amyotrophic Lateral Sclerosis Gene Discovery

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is the most prominent motor neuron disease in humans. Its etiology consists of progressive motor neuron degeneration resulting in a rapid decline in motor function starting in the limbs or bulbar muscles and eventually fatally impairing central organs most typically resulting in loss of respiration. Pathogenic variants in 4 main genes, SOD1, TARDBP, FUS, and C9orf72, have been well characterized as causative for more than a decade now. However, these only account for a small fraction of all ALS cases. In this review, we highlight many additional variants that appear to be causative or confer increased risk for ALS, and we reflect on the technologies that have led to these discoveries. Next, we call attention to new challenges and opportunities for ALS and suggest next steps to increase our understanding of ALS genetics. Finally, we conclude with a synopsis of gene therapy paradigms and how increased understanding of ALS genetics can lead us to developing effective treatments. Ultimately, a consolidated update of the field can provide a launching point for researchers and clinicians to improve our search for ALS-related genes, defining pathogenic mechanisms, form diagnostics, and develop therapies.

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“…Altered histone acetylation has been associated with reduced neuronal survival and pathological CNS conditions, including stroke, PD, AD and Huntington's disease (Konsoula and Barile, 2012;Uzdensky and Demyanenko 2021). A growing body of evidence suggests a possible role for a dysregulation of epigenetic mechanisms, including histone acetylation, also in the occurrence and progression of ALS (Jimenez-Pacheco et al, 2017;Bennett et al, 2019;Zhang et al, 2022). For example, overexpression of FUS or TDP-43 in yeast ALS proteinopathy models resulted in histone hypo-and hyperacetylation, respectively, suggesting that each proteinopathy may correspond to a specific alteration of histone acetylation (Chen K et al, 2018).…”

Section: The Pathogenic Role Of Anomalous Acetylation Of Nf-κb/rela A...mentioning

confidence: 99%

Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis

Parrella¹,

Porrini²,

Scambi³

et al. 2022

Front. Pharmacol.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.

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Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Cited by 81 publications

References 133 publications

C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response

C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response

Progress in Amyotrophic Lateral Sclerosis Gene Discovery

Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis

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