Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing

Zhang, Qingyang; Zhang, Juan; Jin, Yufeng; Li, Xiaohui; Liu, Hongda; Ma, Xiaolin; Wang, Chao; He, Keqiang; Zhang, Wei; Yuan, Junhua; Zhao, Yingjun; Xu, Huaxi; Liu, Qiang

doi:10.1186/s13024-021-00485-w

Cited by 18 publications

(5 citation statements)

References 71 publications

(83 reference statements)

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“…The novel object recognition test was conducted as described previously, with minor modifications ( Lueptow, 2017 ; Zhang et al, 2021 ). Before the test, mice were allowed to explore the test chamber (with a dimension of 45 cm × 45 cm × 40 cm; RWD Life Science) for 5 min/day for 2 days.…”

Section: Methodsmentioning

confidence: 99%

Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders

Zhang

et al. 2022

Front. Aging Neurosci.

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Perioperative neurocognitive disorders (PNDs) are a type of cognitive dysfunction occurring with a higher incidence in elderly patients. However, the pathological mechanism of PND and effective treatment remain elusive. We generated a PND mouse model by providing wild-type mice with surgical trauma; in our case, we used tibial fracture to investigate PND pathology. Mice aged 7–8 months were randomly divided into two groups: the surgery (tibial fracture) group and the control (sham) group. All mice were subjected to anesthesia. We examined the transcriptome-wide response in the hippocampus, a brain region that is tightly associated with memory formation, of control mice and mice subjected to surgical trauma at day 1 and day 3 after the surgical procedure. We observed reduced transcript levels of respiratory complex components as early as day 1 after surgery, and subsequent protein changes were found at day 3 after surgical trauma. Consequently, the activities of respiratory complexes were reduced, and adenosine triphosphate (ATP) production was decreased in the hippocampus of mice with surgical operations, supporting that respiratory chain function was impaired. In support of these conclusions, the mitochondrial membrane potential (MMP) levels were decreased, and the reactive oxygen species (ROS) levels were significantly increased. Mechanistically, we demonstrated that surgery induced a significant increase in cytokine IL-1β levels at day 1 after surgery, which concomitantly occurred with transcript changes in respiratory complex components. We further uncovered that transcription factors PGC-1α and NRF-1 were responsible for the observed transcript changes in mitochondrial complex components. Importantly, HT22 cells treated with the cytokine IL-1β resulted in similar reductions in PGC-1α and NRF-1, leading to a reduction of both the transcript and protein levels of respiratory complex subunits. Consequently, respiratory function was impaired in HT22 cells treated with IL-1β. Taken together, we demonstrated that reductions in respiratory complex components and subsequent impairment in mitochondrial functions serve as a novel mechanism for PND pathology, providing a potential therapeutic target for PND treatment.

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Section: Methodsmentioning

confidence: 99%

Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders

Zhang

et al. 2022

Front. Aging Neurosci.

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“…For instance, RBM24 interacts with the ISE and promotes the retention of muscle‐specific exons in striated muscle 81 . Notably, certain atypical splicing factors like U2AF65, SF3B3 and SF1 regulate alternative splicing by directly binding to pre‐mRNA rather than SREs 82,83 …”

Section: Alternative Splicingmentioning

confidence: 99%

“…81 Notably, certain atypical splicing factors like U2AF65, SF3B3 and SF1 regulate alternative splicing by directly binding to pre-mRNA rather than SREs. 82,83…”

Section: Mechanisms Of Pre-mrna Alternative Splicingmentioning

confidence: 99%

Crosstalk between m6A modification and alternative splicing during cancer progression

Zhu,

Huo,

Zhang

et al. 2023

Clinical & Translational Med

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BackgroundN6‐methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and recognised by m6A‐binding proteins. This modification significantly influences carious facets of RNA metabolism and plays a pivotal role in cellular and physiological processes.Main bodyPre‐mRNA alternative splicing, a process that generates multiple splice isoforms from multi‐exon genes, contributes significantly to the protein diversity in mammals. Moreover, the presence of crosstalk between m6A modification and alternative splicing, with m6A modifications on pre‐mRNAs exerting regulatory control, has been established. The m6A modification modulates alternative splicing patterns by recruiting specific RNA‐binding proteins (RBPs) that regulate alternative splicing or by directly influencing the interaction between RBPs and their target RNAs. Conversely, alternative splicing can impact the deposition or recognition of m6A modification on mRNAs. The integration of m6A modifications has expanded the scope of therapeutic strategies for cancer treatment, while alternative splicing offers novel insights into the mechanistic role of m6A methylation in cancer initiation and progression.ConclusionThis review aims to highlight the biological functions of alternative splicing of m6A modification machinery and its implications in tumourigenesis. Furthermore, we discuss the clinical relevance of understanding m6A‐dependent alternative splicing in tumour therapies.

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“…Thus, for species such as mouse, Drosophila, and rhesus macaque, high circRNA stability may contribute to increased levels of circRNAs during brain aging. Additionally, changes in splicing patterns have been identified during aging [61,62]. Since alternative splicing plays an important role in circRNA biogenesis [2,42], alterations in alternative splicing may contribute to changes in their levels during aging.…”

Section: Mechanisms Underlying the Regulation Of Circrna Levels Durin...mentioning

confidence: 99%

Circular RNAs: emerging players in brain aging and neurodegenerative diseases

Zhao

Yan

et al. 2022

The Journal of Pathology

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Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases.

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Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing

Cited by 18 publications

References 71 publications

Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders

Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders

Crosstalk between m6A modification and alternative splicing during cancer progression

Circular RNAs: emerging players in brain aging and neurodegenerative diseases

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