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

Eysert, Fanny; Coulon, Audrey; Boscher, Emmanuelle; Vreulx, Anaїs-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:10.1038/s41380-020-00926-w

Cited by 33 publications

(26 citation statements)

References 46 publications

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“…In the postsynaptic membrane, Camk2b and Grip1 regulate the intracellular trafficking of AMPA receptors [ 57 , 58 , 59 ], Sorbs1 participates in the clustering of acetylcholine receptors [ 60 ], and Gabrg2 regulates the GABAergic signaling [ 61 ]. Fermt2 encodes a scaffolding protein that regulates axonal growth, PPF, and LTP [ 62 ]. Many of the affected genes (e.g., Add3 , Cacna1d , Camk2b , Fermt2, Gabrg2 , Grip1 , Kcnd3 , Sorbs1 , and Stx2 ) are regulated by MBNL proteins, and they are also misregulated in other DM1 mouse models and human tissues [ 47 , 63 , 64 , 65 , 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

Potier

Lallemant

Parrot

et al. 2022

IJMS

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Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction.

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Section: Discussionmentioning

confidence: 99%

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

Potier

Lallemant

Parrot

et al. 2022

IJMS

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“…33 The scaffolding protein FERMT2 encoded by gene FERMT2 (Fermitin family homolog 2) is critically involved in integrin-mediated cell-extracellular matrix interaction and controlling for axonal growth and synaptic plasticity. 34,35 A study using the Drosophila model of AD has shown that FERMT2 plays a role in the modulation of tau toxicity. 36 In addition, knockdown or knockout of FERMT2 in familiar AD human neurons has been shown to reduce the levels of phosphorylated tau.…”

Section: Discussionmentioning

confidence: 99%

Identification of Sex-Specific Genetic Variants Associated With Tau PET

et al. 2022

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Background and ObjectivesImportant sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET.MethodsFour hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and18F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons:BIN1,MS4A6A,DNAJA2,FERMT2,APOC1,APOC1P1,FAM193B,C2orf47,TYW5, andCR1.Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status,APOEε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.ResultsWe identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 withinDNAJA2, rs113357081 withinFERMT2, and rs74614106 withinTYW5. In men, we also identified 3 loci withinCR1associated with tau deposits: rs115096248, rs113698814, and rs78150633.DiscussionOur findings revealed sex-specific genetic variants associated with tau deposition independent ofAPOEε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.

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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][118][119][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 And mentioning

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

Cited by 33 publications

References 46 publications

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

Identification of Sex-Specific Genetic Variants Associated With Tau PET

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

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