Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

Zbinden, Aurélie; Pérez‐Berlanga, Manuela; Rossi, Pierre De; Polymenidou, Magdalini

doi:10.1016/j.devcel.2020.09.014

Cited by 341 publications

(269 citation statements)

References 328 publications

(571 reference statements)

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“…Dynamic phase separated membraneless organelles including SGs are induced upon varied stress-stimuli (infectious or non-infectious) and are implicated in spatiotemporal control of various cellular functions including formation of signalling complexes, clustering of vesicles, sorting and trafficking of cargo [244]. Phase separated biomolecular condensates are becoming increasingly linked to developmental and pathological pathways [245][246][247][248][249]. We proposed proteases as novel stressors that can have diverse outcomes when present at varying concentrations (protease-antiprotease balance is crucial for driving tissue repair or fibrotic phenotypes).…”

Section: Future Perspectives and Summarymentioning

confidence: 99%

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

Sharma¹,

Kaushal²,

Rawat³

et al. 2021

Extracellular Matrix - Developments and Therapeutics

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Diverse internal and external pathologic stimuli can trigger cellular stress response pathways (CSRPs) that are usually counteracted by intrinsic homeostatic machinery, which responds to stress by initiating complex signaling mechanisms to eliminate either the stressor or the damaged cells. There is growing evidence that CSRPs can have context-dependent homeostatic or pathologic functions that may result in tissue fibrosis under persistence of stress. CSRPs can drive intercellular communications through exosomes (trafficking and secretory pathway determinants) secreted in response to stress-induced proteostasis rebalancing. The injured tissue environment upon sensing the stress turns on a precisely orchestrated network of immune responses by regulating cytokine-chemokine production, recruitment of immune cells, and modulating fibrogenic niche and extracellular matrix (ECM) cross-talk during fibrotic pathologies like cardiac fibrosis, liver fibrosis, laryngotracheal stenosis, systemic scleroderma, interstitial lung disease and inflammatory bowel disease. Immunostimulatory RNAs (like double stranded RNAs) generated through deregulated RNA processing pathways along with RNA binding proteins (RBPs) of RNA helicase (RNA sensors) family are emerging as important components of immune response pathways during sterile inflammation. The paradigm-shift in RNA metabolism associated interactome has begun to offer new therapeutic windows by unravelling the novel RBPs and splicing factors in context of developmental and fibrotic pathways. We would like to review emerging regulatory nodes and their interaction with CSRPs, and tissue remodeling with major focus on cardiac fibrosis, and inflammatory responses underlying upper airway fibrosis.

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Section: Future Perspectives and Summarymentioning

confidence: 99%

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

Sharma¹,

Kaushal²,

Rawat³

et al. 2021

Extracellular Matrix - Developments and Therapeutics

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“…The highly complex interactions and interplay illustrated in this review may be especially important for the correct organization and functioning of morphologically complex and highly polarized cells such as neurons. Many studies have shown that dysfunction of the cytoskeleton, several membranebound organelles and biomolecular condensates is implicated in neuron dysfunction and neurological disorders (Figure 3; Fowler et al, 2019;Sleigh et al, 2019;Zbinden et al, 2020). However, the role of the complex interactions and interplay between them in disease pathogenesis is much less clear.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…In addition, the role of the cytoskeleton in these contacts and the interplay of these organelles and condensates with the cytoskeleton are just beginning to emerge. Understanding the complex relationship and interplay between the cytoskeleton, membrane-bound organelles and biomolecular condensates is imperative since dysfunction of each of these components and the dysregulation of their interactions are known to be involved in several neurodegenerative diseases including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS) (Fowler et al, 2019;Sleigh et al, 2019;Zbinden et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Complex Interactions Between Membrane-Bound Organelles, Biomolecular Condensates and the Cytoskeleton

Koppers

Özkan

Farı́as

2020

Front. Cell Dev. Biol.

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Membrane-bound and membraneless organelles/biomolecular condensates ensure compartmentalization into functionally distinct units enabling proper organization of cellular processes. Membrane-bound organelles form dynamic contacts with each other to enable the exchange of molecules and to regulate organelle division and positioning in coordination with the cytoskeleton. Crosstalk between the cytoskeleton and dynamic membrane-bound organelles has more recently also been found to regulate cytoskeletal organization. Interestingly, recent work has revealed that, in addition, the cytoskeleton and membrane-bound organelles interact with cytoplasmic biomolecular condensates. The extent and relevance of these complex interactions are just beginning to emerge but may be important for cytoskeletal organization and organelle transport and remodeling. In this review, we highlight these emerging functions and emphasize the complex interplay of the cytoskeleton with these organelles. The crosstalk between membrane-bound organelles, biomolecular condensates and the cytoskeleton in highly polarized cells such as neurons could play essential roles in neuronal development, function and maintenance.

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“…[4,5] Now liquidlike condensed polymer phases in the form of intrinsically disordered protein (IDP) domains exist across as many as 40% of all eukaryotic proteins and these domains are implicated in the emergence of multicellularity. [6] From the nucleolus and nucleopores to ribonucleoprotein granules, disordered protein-rich phases of biopolymer condensates [7] mediate information flow throughout the eukaryotic cell today.…”

Section: Introductionmentioning

confidence: 99%

“…Such network regulation can be observed in biopolymer condensates, which rely on liquidliquid phase separation (LLPS) to establish boundaries based on subtle physicochemical differences between the internal and external environments. [7] A commonly explored case of such biopolymer condensates, the nucleolus, consists of three specialized subcompartments for staged ribosome assembly. [34,35] Each subcompartment, the fibrillar center (FC), the dense FC (DFC), and the globular compartment (GC), contains different IDPs and their respective interactions with rDNA or rRNA collectively mediate the many stages of ribosomal assembly in distinct biophysical environments.…”

Section: Introductionmentioning

confidence: 99%

Capturing nested information from disordered peptide phases

2020

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Anfinsen's dogma emerged from experiments which show that a protein's native 3D folded architecture is encoded within its primary sequence. This insight emerged before almost 40% of eukaryotic proteins were found to contain intrinsically disordered domains with binding partners that are able to template multiple structures and functional outputs. Despite the challenges associated with characterizing such intrinsically disordered protein domains and their interactions with various binding partners, the need to understand how they propagate and regulate context-dependent information now becomes increasingly important. In addition to understanding the complex signaling networks of multicellular organisms, harness their potential will expand the next generation of functional materials. Accordingly, we review progress with model peptides to reveal the rules necessary for precise spatiotemporal assembly of polypeptide materials.

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Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

Cited by 341 publications

References 328 publications

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

Complex Interactions Between Membrane-Bound Organelles, Biomolecular Condensates and the Cytoskeleton

Capturing nested information from disordered peptide phases

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