Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers

Robinson, Hayley; Ali, Sk Imran; Díaz-Hernández, Martha Elena; López-González, Rodrigo

doi:10.3389/fcell.2022.874323

Cited by 2 publications

(2 citation statements)

References 34 publications

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“…Knockout of telomerase leads to telomere shortening and an accelerated ALS phenotype in the SOD1 G93A mice model [ 76 ]. In addition, age-dependent telomere shortening was detected in iPSC motor neurons from C9ORF72 patients [ 77 ]. However, a recent whole genome sequencing study concluded that longer telomeres are a risk factor for ALS and worsen prognosis, including in the brain [ 78 ].…”

Section: Molecular Hallmarks Of Ageing In Alsmentioning

confidence: 99%

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Jagaraj,

Shadfar,

Kashani

et al. 2024

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.

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Section: Molecular Hallmarks Of Ageing In Alsmentioning

confidence: 99%

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Jagaraj,

Shadfar,

Kashani

et al. 2024

Cell. Mol. Life Sci.

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“…Furthermore, it was recently discovered that an age-dependent increase in oxidative stress leads to telomere attrition in the post-mitotic stage of induced pluripotent stem cell (iPSC)-derived motor neurons expressing the C9ORF72 mutation, which is commonly seen in two incurable neurodegenerative diseases, namely amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While there were no changes in the protein expressions of TRF2 and POT1 in neuroepithelial cells and motor neuron progenitors, these protein levels were reduced in two-month-old post-mitotic motor neurons bearing the C9ORF72 mutation, which caused the exposed ends of the chromosomes to trigger the DDR [ 109 ].…”

Section: Oxidative Stressmentioning

confidence: 99%

Exploring the Causal Relationship Between Telomere Biology and Alzheimer’s Disease

Kuan

Fauzi

et al. 2023

Mol Neurobiol

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Telomeres, also known as the “protective caps” of our chromosomes, shorten with each cell cycle due to the end replication problem. This process, termed telomere attrition, is associated with many age-related disorders, such as Alzheimer’s disease (AD). Despite the numerous studies conducted in this field, the role of telomere attrition in the onset of the disease remains unclear. To investigate the causal relationship between short telomeres and AD, this review aims to highlight the primary factors that regulate telomere length and maintain its integrity, with an additional outlook on the role of oxidative stress, which is commonly associated with aging and molecular damage. Although some findings thus far might be contradictory, telomere attrition likely plays a crucial role in the progression of AD due to its close association with oxidative stress. The currently available treatments for AD are only symptomatic without affecting the progression of the disease. The components of telomere biology discussed in this paper have previously been studied as an alternative treatment option for several diseases and have exhibited promising in vitro and in vivo results. Hence, this should provide a basis for future research to develop a potential therapeutic strategy for AD. Graphical Abstract (Created with BioRender.com)

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Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers

Cited by 2 publications

References 34 publications

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Exploring the Causal Relationship Between Telomere Biology and Alzheimer’s Disease

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