Multiomics and artificial intelligence enabled peripheral blood-based prediction of amnestic mild cognitive impairment

Tatara, Yota; Yamazaki, Hiromi; Katsuoka, Fumiki; Chiba, Mitsuru; Saigusa, Daisuke; Kasai, Shuya; Nakamura, Tomohiro; Inoue, Jin; Aoki, Yosuke; Shoji, Miho; Motoike, Ikuko N.; Tamada, Yoshinori; Hashizume, Katsuhito; Shoji, Mikio; Kinoshita, Kengo; Murashita, Koichi; Nakaji, Shigeyuki; Yamamoto, Masayuki; Itoh, Ken

doi:10.1016/j.retram.2022.103367

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…Ribosomes stall during the co-translational transport of APP.C99 in the ER membrane and Are rescued by RQC; however, insufficient RQC adds CAT-tail-like C-terminal extensions onto APP.C99, which are prone to aggregation and cause lysosomal dysfunction [139]. Interestingly, previously, we demonstrated that miR-NAs targeting GCN1 are selectively downregulated in the peripheral blood of patients with amnestic mild cognitive impairment, a pre-disease state of Alzheimer's disease, indicating that GCN1-mediated quality control may be enhanced in amnestic mild cognitive impairment [140]. In addition, whole-blood transcriptome and plasma metabolome analyses suggested an AAS response in undetermined cells in the peripheral blood.…”

Section: Potential Role Of Gcn1 In Neurodegenerative Diseasesmentioning

confidence: 83%

Emerging Role of GCN1 in Disease and Homeostasis

Tatara,

Kasai,

Kokubu

et al. 2024

Preprint

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GCN1 is recognized as a factor that is essential for the activation of GCN2, which is a sensor of amino acid starvation. This function is evolutionarily conserved from yeast to higher eukaryotes. However, recent studies have revealed non-canonical functions of GCN1 that are independent of GCN2, such as its participation in cell proliferation, apoptosis, and the immune response, beyond the borders of species. Although it is known that GCN1 and GCN2 interact with ribosomes to accomplish amino acid starvation sensing, recent studies have reported that GCN1 binds to disomes (i.e. ribosomes that collide each other), thereby regulating both the co-translational quality control and stress response. We propose that GCN1 regulates ribosome-mediated signaling by dynamically changing its partners among RWD domain-possessing proteins via unknown mechanisms. We recently demonstrated that GCN1 is essential for cell proliferation and whole-body energy regulation in mice. However, the manner in which ribosome-initiated signaling via GCN1 is related to various physiological functions warrants clarification. GCN1-mediated mechanisms and its interaction with other quality control and stress response signals should be important for proteostasis during aging and neurodegenerative diseases, and may be targeted for drug development.

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Section: Potential Role Of Gcn1 In Neurodegenerative Diseasesmentioning

confidence: 83%

Emerging Role of GCN1 in Disease and Homeostasis

Tatara,

Kasai,

Kokubu

et al. 2024

Preprint

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“…In this respect, we have recently hypothesized that CD8+ T emra cells migrating into peripheral tissues, including the CNS, may fine‐tune CNS homeostasis through the secretion of IFN‐ɣ, TGF‐β, and IL‐10, and the interaction between HLA class I molecules and inhibitory NK receptors 54 . Interestingly, a recent multiomics study with peripheral blood samples from amnestic mild cognitive impairment (aMCI) patients has revealed that T cells with immunosuppressor function (without ascertaining whether CD4+ or CD8+, or both) represent a biomarker associated with aMCI 55 …”

Section: Discussionmentioning

confidence: 99%

“…54 Interestingly, a recent multiomics study with peripheral blood samples from amnestic mild cognitive impairment (aMCI) patients has revealed that T cells with immunosuppressor function (without ascertaining whether CD4+ or CD8+, or both) represent a biomarker associated with aMCI. 55…”

Section: Relevance Of the Hla-a23 Or Hla-a24 Serotypes In The Context...mentioning

confidence: 99%

HLA‐A23/HLA‐A24 serotypes and dementia interaction in the elderly: Association with increased soluble HLA class I molecules in plasma

Cardoso,

Lourenço‐Gomes,

Esgalhado

et al. 2023

HLA

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MHC class I molecules regulate brain development and plasticity in mice and HLA class I molecules are associated with brain disorders in humans. We investigated the relationship between plasma‐derived soluble human HLA class I molecules (sHLA class I), HLA class I serotypes and dementia. A cohort of HLA class I serotyped elderly subjects with no dementia/pre‐dementia (NpD, n = 28), or with dementia (D, n = 28) was studied. Multivariate analysis was used to examine the influence of dementia and HLA class I serotype on sHLA class I levels, and to compare sHLA class I within four groups according to the presence or absence of HLA‐A23/A24 and dementia. HLA‐A23/A24 and dementia, but not age, significantly influenced the level of sHLA class I. Importantly, the concurrent presence of HLA‐A23/A24 and dementia was associated with higher levels of sHLA class I (p < 0.001). This study has shown that the simultaneous presence of HLA‐A23/HLA‐A24 and dementia is associated with high levels of serum sHLA class I molecules. Thus, sHLA class I could be considered a biomarker of neurodegeneration in certain HLA class I carriers.

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“…Ribosomes stall during the co-translational transport of APP.C99 in the ER membrane and Are rescued by RQC; however, insufficient RQC adds CAT-tail-like C-terminal extensions onto APP.C99, which are prone to aggregation and cause lysosomal dysfunction [ 139 ]. Interestingly, previously, we demonstrated that miRNAs targeting GCN1 are selectively downregulated in the peripheral blood of patients with amnestic mild cognitive impairment, a pre-disease state of Alzheimer’s disease, indicating that GCN1-mediated quality control may be enhanced in amnestic mild cognitive impairment [ 140 ]. In addition, whole-blood transcriptome and plasma metabolome analyses suggested an AAS response in undetermined cells in the peripheral blood.…”

Section: Potential Role Of Gcn1 In Aging and Diseasementioning

confidence: 99%

Emerging Role of GCN1 in Disease and Homeostasis

Tatara,

Kasai,

Kokubu

et al. 2024

IJMS

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GCN1 is recognized as a factor that is essential for the activation of GCN2, which is a sensor of amino acid starvation. This function is evolutionarily conserved from yeast to higher eukaryotes. However, recent studies have revealed non-canonical functions of GCN1 that are independent of GCN2, such as its participation in cell proliferation, apoptosis, and the immune response, beyond the borders of species. Although it is known that GCN1 and GCN2 interact with ribosomes to accomplish amino acid starvation sensing, recent studies have reported that GCN1 binds to disomes (i.e., ribosomes that collide each other), thereby regulating both the co-translational quality control and stress response. We propose that GCN1 regulates ribosome-mediated signaling by dynamically changing its partners among RWD domain-possessing proteins via unknown mechanisms. We recently demonstrated that GCN1 is essential for cell proliferation and whole-body energy regulation in mice. However, the manner in which ribosome-initiated signaling via GCN1 is related to various physiological functions warrants clarification. GCN1-mediated mechanisms and its interaction with other quality control and stress response signals should be important for proteostasis during aging and neurodegenerative diseases, and may be targeted for drug development.

show abstract

Multiomics and artificial intelligence enabled peripheral blood-based prediction of amnestic mild cognitive impairment

Cited by 5 publications

References 43 publications

Emerging Role of GCN1 in Disease and Homeostasis

Emerging Role of GCN1 in Disease and Homeostasis

HLA‐A23/HLA‐A24 serotypes and dementia interaction in the elderly: Association with increased soluble HLA class I molecules in plasma

Emerging Role of GCN1 in Disease and Homeostasis

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