RNA binding proteins in senescence: A potential common linker for age-related diseases?

Varesi, Angelica; Campagnoli, Lucrezia Irene Maria; Barbieri, Annalisa; Rossi, Lorenzo; Ricevuti, Giovanni; Esposito, Ciro; Chirumbolo, Salvatore; Marchesi, Nicoletta; Pascale, Alessia

doi:10.1016/j.arr.2023.101958

Cited by 6 publications

(5 citation statements)

References 353 publications

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“…However, here we show that, amongst such protein folding factors, DNAJB5, HSP90AB1, CALR, and CDC37 all exhibit increased levels in the cytoplasm of hTDP-43 ΔNLS -positive neurons in the primary motor cortex of rNLS8 mice at disease onset. Further, we demonstrate that this increase in abundance is mediated by currently uncharacterized post-transcriptional mechanisms (possibly via non-coding RNAs 70 or RBPs 71 ), given that there was no increase in transcript level to correlate with the heightened protein abundance. Previous studies have also reported a divergence of protein levels from RNA levels of some HSPs, with increases in HSPB1 in SOD1 G93A mice being accompanied by no change in Hspb1 transcripts 72 .…”

Section: Discussionmentioning

confidence: 75%

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

San Gil,

Pascovici,

Venturato

et al. 2024

Nat Commun

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Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 75%

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

San Gil,

Pascovici,

Venturato

et al. 2024

Nat Commun

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“…Another candidate hallmark supported by several studies is the dysregulation of RNA processing, a process that regulates gene expression ( Figure 4 ). This hallmark was first proposed in the Copenhagen aging meeting in 2022 ( Schmauck-Medina et al, 2022 ) and then supported by other studies that highlighted the relevance of long non-coding RNAs ( Sherazi et al, 2023 ) and RNA binding proteins ( Varesi et al, 2023 ) in the aging process. These works pointed out that these elements lose their regulation during aging and how the subsequent molecular and cellular changes promote the aging process and its associated diseases ( Sherazi et al, 2023 ; Varesi et al, 2023 ).…”

Section: Introductionmentioning

confidence: 71%

“…This hallmark was first proposed in the Copenhagen aging meeting in 2022 ( Schmauck-Medina et al, 2022 ) and then supported by other studies that highlighted the relevance of long non-coding RNAs ( Sherazi et al, 2023 ) and RNA binding proteins ( Varesi et al, 2023 ) in the aging process. These works pointed out that these elements lose their regulation during aging and how the subsequent molecular and cellular changes promote the aging process and its associated diseases ( Sherazi et al, 2023 ; Varesi et al, 2023 ). However, a recent review of the field has shown that even if the dysregulation of RNA processing is a promising candidate, there is still not enough evidence of in vivo acceleration or amelioration of aging through interventions targeting RNA processing ( Harries, 2023 ).…”

Section: Introductionmentioning

confidence: 71%

The hallmarks of aging as a conceptual framework for health and longevity research

Tartiere,

Freije,

López-Otín

2024

Front. Aging

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The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific advances in the field, the complexity of the process has hampered its comprehension. In this context, The Hallmarks of Aging were defined in 2013 with the aim of establishing an organized, systematic and integrative view of this topic, which would serve as a conceptual framework for aging research. Ten years later and promoted by the progress in the area, an updated version included three new hallmarks while maintaining the original scope. The aim of this review is to determine to what extent The Hallmarks of Aging achieved the purpose that gave rise to them. For this aim, we have reviewed the literature citing any of the two versions of The Hallmarks of Aging and conclude that they have served as a conceptual framework not only for aging research but also for related areas of knowledge. Finally, this review discusses the new candidates to become part of the Hallmarks list, analyzing the evidence that supports whether they should or should not be incorporated.

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“…They are also involved in modulation of SG dynamics by interaction with cytoplasmic RNAs and other RBPs. Dysregulation of RBPs also induces metabolic dysfunction, ageing, and senescence [ 291 ].…”

Section: Molecular Hallmarks Of Ageing In Alsmentioning

confidence: 99%

“…Interestingly, degenerating neurons in ALS show similar RNA metabolic defects (RNA processing, modifications and transport) to ageing neurons [ 298 ]. Some of the major proteins dysregulated in ALS are RBPs, including TDP43, FUS, TAF15 and hnRNPA1 [ 28 , 291 ]. TDP43 and FUS mislocalise and aggregate in the cytoplasm in sporadic ALS [ 319 ], which reduces their expression in the nucleus [ 288 ], resulting in loss of essential functions, including splicing and regulation of transcription.…”

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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RNA binding proteins in senescence: A potential common linker for age-related diseases?

Cited by 6 publications

References 353 publications

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

The hallmarks of aging as a conceptual framework for health and longevity research

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

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