Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson’s disease and Lewy body dementia

Asghar, Muhammad; Odeh, Amani; Fattahi, Ahmad Jouni; Henriksson, Alexandra Edwards; Miglar, Aurelie; Khosousi, Shervin; Svenningsson, Per

doi:10.1038/s41598-022-22400-z

Cited by 21 publications

(17 citation statements)

References 52 publications

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“…Telomere elongation has also been associated with schizophrenia (Nieratschker et al, 2013;Zhang et al, 2018), a disorder that genetically overlaps with ALS (McLaughlin et al, 2017). Additionally, longer telomeres are also reported in Parkinson's disease and Lewy body dementia blood and brain (Asghar et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Khleifat

Iacoangeli

Jones

et al. 2022

Front. Cell. Neurosci.

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BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

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Section: Discussionmentioning

confidence: 99%

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Khleifat

Iacoangeli

Jones

et al. 2022

Front. Cell. Neurosci.

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“…Telomere length was shorter in patients with Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies compared to controls. There is also a correlation between the number of mitochondria in the blood and risk of PD ( Asghar et al, 2022 ).…”

Section: Senescence In Neurodegenerative Diseasesmentioning

confidence: 99%

Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases

Shreeya,

Ansari,

Kumar

et al. 2024

Front. Aging

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Senescence is a complicated, multi-factorial, irreversible cell cycle halt that has a tumor-suppressing effect in addition to being a significant factor in aging and neurological diseases. Damaged DNA, neuroinflammation, oxidative stress and disrupted proteostasis are a few of the factors that cause senescence. Senescence is triggered by DNA damage which initiates DNA damage response. The DNA damage response, which includes the formation of DNA damage foci containing activated H2AX, which is a key factor in cellular senescence, is provoked by a double strand DNA break. Oxidative stress impairs cognition, inhibits neurogenesis, and has an accelerated aging effect. Senescent cells generate pro-inflammatory mediators known as senescence-associated secretory phenotype (SASP). These pro-inflammatory cytokines and chemokines have an impact on neuroinflammation, neuronal death, and cell proliferation. While it is tempting to think of neurodegenerative diseases as manifestations of accelerated aging and senescence, this review will present information on brain ageing and neurodegeneration as a result of senescence and DNA damage response.

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“…In fact, several pieces of evidence showed that deregulation of the proteolytic system contributed to the development of both forms of PD [ 68 , 69 ]. Effectively, a hallmark of PD is the presence of aggregated α-synuclein, ubiquitin, neurofilaments, and molecular chaperones, present as an intraneuronal inclusions called Lewy Bodies (LBs), showing that aberrant protein homeostasis results in toxic accumulation of intracellular proteins, leading to neuronal loss [ 70 , 71 ]. In healthy conditions, wild-type α-synuclein is available in its native conformation as soluble monomers, which mediates α-synuclein physiological function in presynaptic terminals [ 72 ].…”

Section: Neuronal and Muscular Alterations Found In Parkinson’s Diseasementioning

confidence: 99%

Exercise-Boosted Mitochondrial Remodeling in Parkinson’s Disease

et al. 2022

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Parkinson’s disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons resulting in dopamine deficiency in the striatum. Given the estimated escalation in the number of people with PD in the coming decades, interventions aimed at minimizing morbidity and improving quality of life are crucial. Mitochondrial dysfunction and oxidative stress are intrinsic factors related to PD pathogenesis. Accumulating evidence suggests that patients with PD might benefit from various forms of exercise in diverse ways, from general health improvements to disease-specific effects and, potentially, disease-modifying effects. However, the signaling and mechanism connecting skeletal muscle-increased activity and brain remodeling are poorly elucidated. In this review, we describe skeletal muscle–brain crosstalk in PD, with a special focus on mitochondrial effects, proposing mitochondrial dysfunction as a linker in the muscle–brain axis in this neurodegenerative disease and as a promising therapeutic target. Moreover, we outline how exercise secretome can improve mitochondrial health and impact the nervous system to slow down PD progression. Understanding the regulation of the mitochondrial function by exercise in PD may be beneficial in defining interventions to delay the onset of this neurodegenerative disease.

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Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson’s disease and Lewy body dementia

Cited by 21 publications

References 52 publications

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases

Exercise-Boosted Mitochondrial Remodeling in Parkinson’s Disease

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