Alzheimer’s genetic risk factor<i>FERMT2</i>(Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner

Eysert, Fanny; Coulon, Audrey; Boscher, Emmanuelle; Vreulx, Anaïs-Camille; Flaig, Amandine; Mendes, Tiago; Hughes, Sandrine; Grenier‐Boley, Benjamin; Hanoulle, Xavier; Demiautte, Florie; Bauer, Charlotte; Marttinen, Mikael; Takalo, Mari; Amouyel, Philippe; Desai, Shruti; Pike, Ian; Hiltunen, Mikko; Checler, Frédéric; Farinelli, Mélissa; Delay, Charlotte; Malmanche, Nicolas; Hébert, Sébastien; Dumont, Julie; Kilinc, Devrim; Lambert, Jean‐Charles; Chapuis, Julien

doi:10.1101/767194

Cited by 4 publications

(4 citation statements)

References 44 publications

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“…Genes that showed the same downwards trend in the AD and COVID-19 groups included FCGR2A, MSR1, TBXAS1, FGL2, GBP2, PLXDC2, MOB3C, PARVG, SYT6, CFD, GALK1, NFKB2, CAPG, PLCG2, APOBR, and C1QA. For example, as a genetic risk factor for AD, FERMT2 controls axonal growth and synaptic plasticity in an APP-dependent manner (38). In addition, previous association studies have provided evidence for the associations of HLA-DRB1/DQB1 alleles with AD (39).…”

Section: Discussionmentioning

confidence: 99%

Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer’s disease

Guo

Wang

et al. 2022

Front. Immunol.

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Alzheimer’s disease (AD)-like cognitive impairment, a kind of Neuro-COVID syndrome, is a reported complication of SARS-CoV-2 infection. However, the specific mechanisms remain largely unknown. Here, we integrated single-nucleus RNA-sequencing data to explore the potential shared genes and pathways that may lead to cognitive dysfunction in AD and COVID-19. We also constructed ingenuity AD-high-risk scores based on AD-high-risk genes from transcriptomic, proteomic, and Genome-Wide Association Studies (GWAS) data to identify disease-associated cell subtypes and potential targets in COVID-19 patients. We demonstrated that the primary disturbed cell populations were astrocytes and neurons between the above two dis-eases that exhibit cognitive impairment. We identified significant relationships between COVID-19 and AD involving synaptic dysfunction, neuronal damage, and neuroinflammation. Our findings may provide new insight for future studies to identify novel targets for preventive and therapeutic interventions in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer’s disease

Guo

Wang

et al. 2022

Front. Immunol.

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“…[ 76,82 ] Indeed, previous studies have implicated crucial roles of PINCH‐1 and kindlin‐2 in the neurologic and cardiovascular diseases. [ 117–120 ] It will be interesting to test in future studies to what extent the signaling pathway delineated in this essay contributes to the pathogenesis and progression of neurologic and cardiovascular diseases and if so, the benefits of targeting the PINCH‐1 and kindlin‐2 signaling pathway for alleviation of the progression of these human diseases.…”

Section: Pinch‐1‐ and Kindlin‐2‐mediated Regulation Of Proline Biosynthesis May Serve As A Therapeutic Target For Control Of Fibrosis Andmentioning

confidence: 99%

How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

Chen

Guo

2021

BioEssays

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We propose a signaling pathway in which cell-extracellular matrix (ECM) adhesion components PINCH-1 and kindlin-2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH-1 expression via integrin signaling, which suppresses dynamin-related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin-2 translocation into mitochondria and interaction with Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1). Kindlin-2 interaction with PYCR1 protects the latter from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH-1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. K E Y W O R D Scancer, collagen, extracellular mechano-environment, fibrosis, focal adhesion proteins, mitochondrial dynamics, proline biosynthesis OMM, outer mitochondrial membrane; P5C, Δ 1 -pyrroline-5-carboxylate; P5CS, Δ 1 -pyrroline-5-carboxylate synthase; PH, pleckstrin homology; PYCR, Δ 1 -pyrroline-5-carboxylate reductase; ROS, reactive oxygen species; TCA, tricarboxylic acid; TGF, transforming growth factor as an electron donor. Proline biosynthesis are influenced by both the availability of the substrate (i.e. P5C) and the expression levels and activities of the enzyme (i.e. PYCR). Three isoforms of PYCR, namely PYCR1, 2, and L, have been identified in mammals. [1,4] PYCR1 and 2 share a high level (approximately 84%) of similarity in amino acid sequence, whereas the similarity in amino acid sequence between PYCRL and PYCR1/2 is considerably lower (approximately 45%).All three PYCRs are encoded by genes (i.e. PYCR1, 2, and L) in the nuclei. However, after PYCR1 and 2 proteins are synthesized, they are transported from the cytosol into mitochondria where they catalyze the final step in proline biosynthesis (i.e. conversion of P5C to proline).

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“…Global deletion of Kindlin-2 expression causes early embryonic lethality at E7.5 in mice [13]. Furthermore, Kindlin-2 and other FA related proteins are widely involved in the control of the development and function of skeleton, kidney, heart and other organs and tissues [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] through both integrin-dependent and integrin-independent mechanisms. In this study, by utilizing biochemical and genetic mouse approaches, we establish that Kindlin-2 acts as a potent inhibitor of the TNF/NF-κB-caspase 8 pathway in hepatocytes and plays an important role in maintaining normal liver development and function.…”

Section: Introductionmentioning

confidence: 99%

Kindlin-2 inhibits TNF/NF-κB-caspase 8 pathway in hepatocytes to maintain liver development and function

Gao¹,

Zhong²,

Zhou

et al. 2022

Preprint

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Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss.Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.

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Alzheimer’s genetic risk factorFERMT2(Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner

Cited by 4 publications

References 44 publications

Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer’s disease

Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer’s disease

How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

Kindlin-2 inhibits TNF/NF-κB-caspase 8 pathway in hepatocytes to maintain liver development and function

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