Cellular senescence in the aging brain: A promising target for neurodegenerative diseases

Sahu, Manas Ranjan; Rani, Linchi; Subba, Rhea; Mondal, Amal Chandra

doi:10.1016/j.mad.2022.111675

Cited by 41 publications

(30 citation statements)

References 196 publications

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“…Interestingly, apoptotic cell death is one of the major pathological signs in Cstb –/– cerebellum ( Pennacchio et al, 1998 ) where oxidative damage has even been described, although not on DNA level ( Lehtinen et al, 2009 ). Of note, oxidative stress is also a common inducer of senescence ( Sahu et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Daura

Tegelberg²,

Hakala³

et al. 2022

Front. Mol. Neurosci.

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Cystatin B (CSTB) is a cysteine cathepsin inhibitor whose biallelic loss-of-function mutations in human result in defects in brain development and in neurodegeneration. The physiological function of CSTB is largely unknown, and the mechanisms underlying the human brain diseases remain poorly understood. We previously showed that CSTB modulates the proteolysis of the N-terminal tail of histone H3 (H3cs1) during in vitro neurogenesis. Here we investigated the significance of this mechanism in postnatal mouse brain. Spatiotemporal analysis of H3cs1 intensity showed that while H3cs1 in wild-type (wt) mice was found at varying levels during the first postnatal month, it was virtually absent in adult brain. We further showed that the high level of H3cs1 coincides with chromatin association of de novo synthesized cathepsin L suggesting a role for nuclear cathepsin L in brain development and maturation. On the contrary, the brains of Cstb–/– mice showed sustained H3cs1 proteolysis to adulthood with increased chromatin-associated cathepsin L activity, implying that CSTB regulates chromatin-associated cathepsin L activity in the postnatal mouse brain. As H3 tail proteolysis has been linked to cellular senescence in vitro, we explored the presence of several cellular senescence markers in the maturing Cstb–/– cerebellum, where we see increased levels of H3cs1. While several markers showed alterations in Cstb–/– mice, the results remained inconclusive regarding the association of deficient CSTB function with H3cs1-induced senescence. Together, we identify a molecular role for CSTB in brain with implications for brain development and disease.

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Section: Discussionmentioning

confidence: 99%

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Daura

Tegelberg²,

Hakala³

et al. 2022

Front. Mol. Neurosci.

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“…Microglia, astrocytes, brain endothelial cells, and other CNS cell types show evidence of senescence and increased expression of senescence factors ( 167 , 168 ). The expression of senescent factors, SASPs in particular, creates an inflammatory milieu within the brain believed to modulate neuroimmune processes while also compromising the integrity of the BBB ( 169 , 170 ). The aggregation of misfolded proteins, including Aβ plaques and tau neurofibrillary tangles, may also promote neuronal and glial senescent phenotypes ( 171 ), as do other common facets of neurodegeneration, such as mitochondrial dysfunction and abnormal proteostasis ( 22 , 172 , 173 ).…”

Section: Inflammation and The Aging Brainmentioning

confidence: 99%

Connecting aging biology and inflammation in the omics era

Walker¹,

Basisty²,

Wilson³

et al. 2022

Journal of Clinical Investigation

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Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

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“…Finally, cellular senescence is a core homeostatic event that provides yet another, age- and state-dependent substrate for neurodegeneration and the development of diseases like AD and PD [ 141 , 142 ]. Cellular senescence in the aging brain affects both neuronal and non-neuronal cells, and it is characterized by a broad array of interconnected disruptions, such as disruptions in autophagy, bioenergetics, and mitochondrial dynamics, as well as the onset of low-grade inflammation [ 142 ].…”

Section: Sars-cov-2 Infection and Pd Overlapsmentioning

confidence: 99%

“…Cellular senescence in the aging brain affects both neuronal and non-neuronal cells, and it is characterized by a broad array of interconnected disruptions, such as disruptions in autophagy, bioenergetics, and mitochondrial dynamics, as well as the onset of low-grade inflammation [ 142 ]. This cumulative array of dysfunction culminates in the accumulation of proteopathic seeds, including tau, amyloids, and α-syn, and tissue-wide remodeling [ 141 ]. It has been shown that SARS-CoV-2 infection induces “immunosenescence” and enhances the senescence-associated secretory phenotype (SASP) in infected tissues, via disruption of host antiviral mechanisms, such as interferon signaling pathways [ 143 , 144 , 145 ].…”

Section: Sars-cov-2 Infection and Pd Overlapsmentioning

confidence: 99%

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

Mysiris

Vavougios

Karamichali

et al. 2022

IJMS

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

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Cellular senescence in the aging brain: A promising target for neurodegenerative diseases

Cited by 41 publications

References 196 publications

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Connecting aging biology and inflammation in the omics era

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

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