Alzheimer's Disease-Linked Presenilin Mutation (PS1M146L) Induces Filamin Expression and γ-Secretase Independent Redistribution

Lü, Qun; Ding, Kai; Frosch, Matthew P.; Jones, Shiloh B.; Wolfe, Michael S.; Xia, Weiming; Lanford, George W.

doi:10.3233/jad-2010-100585

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…Our results suggest that hypoxia induced the functional coupling of Drp1 and FLNa to enhance mitochondrial fission, and cilnidipine selectively inhibited the hypoxia-induced Drp1-FLNa interaction. Because FLNa is ubiquitously distributed and also correlated with cancer and Alzheimer's disease (63,64), elucidation of the universality of the Drp1-FLNa interaction for mitochondrial quality control may contribute to expanded approval of cilnidipine for other mitochondriarelated diseases.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence

et al. 2018

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Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission-associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development. , Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence

et al. 2018

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“…Presenilin protein is well known for its association with AD [179, 180]. It is a component of γ -secretase enzymes, which are responsible for cleaving amyloid precursor protein (APP) into amyloid beta (A β ).…”

Section: Inflammatory Signaling At the Mam Interfacementioning

confidence: 99%

Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

Thoudam

Jeon

et al. 2016

Mediators of Inflammation

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Inflammation is considered to be one of the most critical factors involved in the development of complex metabolic diseases such as type 2 diabetes, cancer, and cardiovascular disease. A few decades ago, the discovery of mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) was followed by the identification of its roles in regulating cellular homeostatic processes, ranging from cellular bioenergetics to apoptosis. MAM provides an excellent platform for numerous signaling pathways; among them, inflammatory signaling pathways associated with MAM play a critical role in cellular defense during pathogenic infections and metabolic disorders. However, induction of MAM causes deleterious effects by amplifying mitochondrial reactive oxygen species generation through increased calcium transfer from the ER to mitochondria, thereby causing mitochondrial damage and release of mitochondrial components into the cytosol as damage-associated molecular patterns (DAMPs). These mitochondrial DAMPs rapidly activate MAM-resident inflammasome components and other inflammatory factors, which promote inflammasome complex formation and release of proinflammatory cytokines in pathological conditions. Long-term stimulation of the inflammasome instigates chronic inflammation, leading to the pathogenesis of metabolic diseases. In this review, we summarize the current understanding of MAM and its association with inflammation-mediated metabolic diseases.

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“…FlnA directly interacts with presenilins (85), and mutations in presenilin genes PS1 and PS2 account for approximately 50% of early‐onset familial AD (86). Again, PS1 mutation (PS1M146L), which often occurs in early‐onset AD, enhances FlnA expression (87). In addition, FlnA and myosin VI colocalize with fibrillary Tau protein in AD (88).…”

Section: Role Of Flna In Ar Action: From Cell Motility To Neuronal DImentioning

confidence: 99%

Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis

2016

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In this review, we focus on the role played by the protein partners of ligand-activated extranuclear androgen receptor (AR) in the final effects of hormone action, such as proliferation, migration, and neuritogenesis. The choice of AR partner, at least in part, depends on cell type. Androgen-activated receptor directly associates with cytoplasmic Src tyrosine kinase in epithelial cells, whereas in mesenchymal and neuronal cells, it prevalently interacts with filamin A. In the former, proliferation represents the final hormonal outcome, whereas in the latter, either migration or neuritogenesis, respectively, occurs. Furthermore, AR partner filamin A is replaced with Src when mesenchymal cells are stimulated with very low androgen concentrations. Consequently, the migratory effect is replaced by mitogenesis. Use of peptides that prevent receptor/partner assembly abolishes the effects that are dependent on their association and offers new therapeutic approaches to AR-related diseases. Perturbation of migration is often associated with metastatic spreading in cancer. In turn, cell cycle aberration causes tumors to grow faster, whereas toxic signaling triggers neurodegenerative events in the CNS. Here, we provide examples of new tools that interfere in rapid androgen effects, including migration, proliferation, and neuronal differentiation, together with their potential therapeutic applications in AR-dependent diseases-mainly prostate cancer and neurodegenerative disorders.-Castoria, G., Auricchio, F., Migliaccio, A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis.

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Alzheimer's Disease-Linked Presenilin Mutation (PS1M146L) Induces Filamin Expression and γ-Secretase Independent Redistribution

Cited by 12 publications

References 38 publications

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence

Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis

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