Willin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer’s Disease

Chen, Doris; Yu, Wanjia; Aitken, Laura; Gunn‐Moore, Frank

doi:10.3390/cells10113024

Cited by 11 publications

(7 citation statements)

References 157 publications

(288 reference statements)

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“…Because the cell-type specific nature of the consequences of altered Willin/FRMD6 expression have previously been noted [51] and because the effects of Willin/FRMD6 modulation in primary central nervous system neurons are presently unknown, we confirmed the role of Willin/FRMD6 in modulating mitochondrial function in primary mouse cortical and hippocampal neurons. Consistent with the results in HT-22 cells, exposure of primary neurons to Aβ resulted in decreased Willin/FRMD6 expression, which was ameliorated by pre-treatment with mitoTEMPO (Figure 5A).…”

Section: Willin/frmd6 Knockdown Induces Mitochondrial Dysfunction In ...supporting

confidence: 73%

Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity

Chen

Aitken

et al. 2022

Cells

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Willin/FRMD6 has been reported as a potential Alzheimer’s disease (AD) risk gene in a series of genome-wide association and neuroimaging studies; however, the mechanisms underlying its potential role in AD pathogenesis remain unknown. Here, we demonstrate the direct effects of Aβ on Willin/FRMD6 expression and position mitochondrial oxidative stress as a novel potential mechanism underlying the role of Willin/FRMD6 in AD pathogenesis. Specifically, using mouse hippocampal HT-22 cells and primary mouse neurons, we show that Aβ induces downregulation of Willin/FRMD6 protein expression. Furthermore, we demonstrate that Willin/FRMD6 knockdown leads to mitochondrial dysfunction and fragmentation, as well as upregulation of ERK1/2 signaling, both of which are reported to be key early features of AD pathogenesis. Importantly, increasing Willin/FRMD6 expression was able to rescue Aβ-induced abnormalities in mitochondrial morphology, function, and energetics. Thus, enhancing Willin/FRMD6 expression holds potential as a therapeutic strategy for protecting against Aβ-induced mitochondrial and neuronal dysfunction.

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Section: Willin/frmd6 Knockdown Induces Mitochondrial Dysfunction In ...supporting

confidence: 73%

Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity

Chen

Aitken

et al. 2022

Cells

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“…2c ). FRMD6 regulates actin dynamics 44 ; hence, its preferential localization in dendrites suggests that cytoskeletal processes are modified in response to neuronal activation.…”

Section: Resultsmentioning

confidence: 99%

Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

Hacisuleyman,

Hale,

Noble

et al. 2024

Nat Neurosci

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Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to monitor how depolarization impacts local dendritic biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increased the translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long-term potentiation, cell signaling and energy metabolism. This activity-dependent translation was accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs were sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.

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“…Increased expression of PLK2 shown in the above work affects cell cycle arrest in granulosa cells, which is necessary for their luteinization in the perovulatory period. The FRMD-6 protein belongs to the FERM superfamily of proteins and has been shown to be involved in the regulation of the Hippo signaling pathway [ 80 ]. This pathway has been shown to significantly affect ovarian follicle development and ovulation in cattle [ 81 , 82 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of genes regulating cell division in porcine follicular granulosa cells

Kulus,

Kranc,

Kulus

et al. 2023

Cell Div

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Background Cell cycle regulation influences the proliferation of granulosa cells and affects many processes related to ovarian folliclular growth and ovulation. Abnormal regulation of the cell cycle can lead to many diseases within the ovary. The aim of this study was to describe the expression profile of genes within granulosa cells, which are related to the formation of the cytoskeleton, organization of cell organelles inside the cell, and regulation of cell division. Established in vitro primary cultures from porcine ovarian follicle granulosa cells were maintained for 48, 96, 144 h and evaluated via microarray expression analysis. Results Analyzed genes were assigned to 12 gene ontology groups "actin cytoskeleton organization", "actin filament organization", "actin filament—based process", "cell—matrix adhesion", "cell—substrate adhesion", "chromosome segregation", "chromosome separation", "cytoskeleton organization", "DNA integrity checkpoint", "DNA replication initiation", "organelle fision", "organelle organization". Among the genes with significantly changed expression, those whose role in processes within the ovary are selected for consideration. Genes with increased expression include (ITGA11, CNN1, CCl2, TPM2, ACTN1, VCAM-1, COL3A1, GSN, FRMD6, PLK2). Genes with reduced expression inlcude (KIF14, TACC3, ESPL1, CDC45, TTK, CDC20, CDK1, FBXO5, NEK2—NIMA, CCNE2). For the results obtained by microarray expressions, quantitative validation by RT-qPCR was performed. Conclusions The results indicated expression profile of genes, which can be considered as new molecular markers of cellular processes involved in signaling, cell structure organization. The expression profile of selected genes brings new insight into regulation of physiological processes in porcine follicular granulosa cells during primary in vitro culture.

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Willin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer’s Disease

Cited by 11 publications

References 157 publications

Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity

Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity

Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

Expression of genes regulating cell division in porcine follicular granulosa cells

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