Telomere shortening leads to earlier age of onset in ALS mice

Linkus, Birgit; Wiesner, Diana; Messner, Matthias; Karabatsiakis, Alexander; Scheffold, Annika; Rudolph, K. Lenhard; Thal, Dietmar Rudolf; Weishaupt, Jochen H.; Ludolph, Albert C.; Danzer, Karin M

doi:10.18632/aging.100904

Cited by 30 publications

(26 citation statements)

References 63 publications

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“…Telomerase-related DNA repair and transcription regulation may contribute to the survival of motor neurons in ALS (Singh et al, 2017 ). Surprisingly, Linkus et al ( 2016 ) found a trend of longer telomeres in microglia from human post-mortem brain tissue with ALS. However, knocking out telomerase in mice accelerated the ALS phenotype (Linkus et al, 2016 ).…”

Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

“…Surprisingly, Linkus et al ( 2016 ) found a trend of longer telomeres in microglia from human post-mortem brain tissue with ALS. However, knocking out telomerase in mice accelerated the ALS phenotype (Linkus et al, 2016 ). The longer telomeres in microglial cells may play a role in microglial proliferation, which contributes to ALS disease progression (Linkus et al, 2016 ).…”

Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

“…However, knocking out telomerase in mice accelerated the ALS phenotype (Linkus et al, 2016 ). The longer telomeres in microglial cells may play a role in microglial proliferation, which contributes to ALS disease progression (Linkus et al, 2016 ). Therefore, the contribution of telomerase in different neural cells in the development of ALS may have distinct mechanisms.…”

Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

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The Emerging Roles for Telomerase in the Central Nervous System

Liu

Nemes

Zhou

2018

Front. Mol. Neurosci.

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Telomerase, a specialized ribonucleoprotein enzyme complex, maintains telomere length at the 3′ end of chromosomes, and functions importantly in stem cells, cancer and aging. Telomerase exists in neural stem cells (NSCs) and neural progenitor cells (NPCs), at a high level in the developing and adult brains of humans and rodents. Increasing studies have demonstrated that telomerase in NSCs/NPCs plays important roles in cell proliferation, neuronal differentiation, neuronal survival and neuritogenesis. In addition, recent works have shown that telomerase reverse transcriptase (TERT) can protect newborn neurons from apoptosis and excitotoxicity. However, to date, the link between telomerase and diseases in the central nervous system (CNS) is not well reviewed. Here, we analyze the evidence and summarize the important roles of telomerase in the CNS. Understanding the roles of telomerase in the nervous system is not only important to gain further insight into the process of the neural cell life cycle but would also provide novel therapeutic applications in CNS diseases such as neurodegenerative condition, mood disorders, aging and other ailments.

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Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

Section: Telomerase and Diseases In The Central Nervous Systemmentioning

confidence: 99%

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The Emerging Roles for Telomerase in the Central Nervous System

Liu

Nemes

Zhou

2018

Front. Mol. Neurosci.

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“…Neuronal cell death and synaptic loss results in the memory loss and other clinical findings in the dementias. Although not a dementia, a similar process may be relevant in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) …”

Section: Part 2: Summary Of the Modelmentioning

confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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“…Exposure to these and other environmental pathogens will accelerate neurodegeneration cascade, which will be accompanied by telomere shortening, a widely known determinant of cell senescence. Indeed, accelerated telomere shortening was observed in ALS mice ( 18 ) and in leukocytes from sporadic ALS patients ( 19 ). Telomere shortening in ALS certainly deserves more attention, since it may be modified by a healthy lifestyle ( 20 ).…”

Section: Age Factormentioning

confidence: 99%