Imperfect asymmetry: The mechanism governing asymmetric partitioning of damaged cellular components during mitosis

Pattabiraman, Sundararaghavan; Kaganovich, Daniel

doi:10.1080/19490992.2015.1014213

Cited by 8 publications

(2 citation statements)

References 87 publications

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“…Recent data indicate that repopulating microglia with PLX5622 mainly derive from proliferation of surviving microglia (Huang et al, 2018), suggesting that regardless of the comparative extent of microglial depletion, the source of the resultant tissue is the same. Moreover, cell proliferation can reset (Bufalino & van der Kooy, 2014; Unruh, Slaughter, & Li, 2013) and rejuvenate (Chishti et al, 2013; Pattabiraman & Kaganovich, 2014) cellular phenotypes. Superficially the new microglial tissue mirrors that found in the young adult brain, as opposed to the aged tissue it replaces.…”

Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…SGs are converted into P-bodies where mRNAs are de-capped and degraded (Kedersha et al 2005) and SFs are converted into a juxta nuclear quality control compartment (JUNQ) and an insoluble protein deposit compartment (IPOD) inclusions where misfolded proteins are either eliminated in the JUNQ or become insoluble aggregates in the IPOD (Amen and Kaganovich 2014;Spokoini et al 2012;Kaganovich et al 2008;Gallina et al 2015). Inclusion structures are not static, and can change their composition, mobility properties, and exchange rates depending on the level and nature of stress (Weisberg et al 2012;Pattabiraman and Kaganovich 2014). Although most of the evidence regarding the biogenesis, function, and properties of JUNQ, IPOD, and SFs come from work done in yeast, there are recent studies suggesting a relatively high degree of conservation for some of these inclusions in higher eukaryotes (Kaganovich et al 2008;Weisberg et al 2012;Ogrodnik et al 2014;Moldavski et al 2015).…”

Section: Stressmentioning

confidence: 99%

Imaging stress

Brielle

Gura

Kaganovich

2015

Cell Stress and Chaperones

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Recent innovations in cell biology and imaging approaches are changing the way we study cellular stress, protein misfolding, and aggregation. Studies have begun to show that stress responses are even more variegated and dynamic than previously thought, encompassing nano-scale reorganization of cytosolic machinery that occurs almost instantaneously, much faster than transcriptional responses. Moreover, protein and mRNA quality control is often organized into highly dynamic macromolecular assemblies, or dynamic droplets, which could easily be mistaken for dysfunctional Baggregates,^but which are, in fact, regulated functional compartments. The nano-scale architecture of stressresponse ranges from diffraction-limited structures like stress granules, P-bodies, and stress foci to slightly larger quality control inclusions like juxta nuclear quality control compartment (JUNQ) and insoluble protein deposit compartment (IPOD), as well as others. Examining the biochemical and physical properties of these dynamic structures necessitates live cell imaging at high spatial and temporal resolution, and techniques to make quantitative measurements with respect to movement, localization, and mobility. Hence, it is important to note some of the most recent observations, while casting an eye towards new imaging approaches that offer the possibility of collecting entirely new kinds of data from living cells. StressProtecting the cell from protein-associated damage is a matter of having the correct proteins at the right place at the right time: the cellular environment changes rapidly in different folding and stress conditions in order to avoid catastrophic consequences of too many misfolded polypeptides or not enough functional proteins. When a cell is exposed to stresses such as heat-shock, cold-shock, osmotic stress, starvation, or amino-acid analogues which cause rampant mutations, the cellular response propagates across the entire network of protein biogenesis.Although much research has focused on how these stresses affect protein synthesis, we are only now beginning to look closely at how stress effects protein localization and distribution. Whereas expression takes time, and is more difficult to accomplish under stress, protein localization is substantially more dynamic and therefore changes in protein distribution can be affected quickly, in time to deal with the stress. Hence, regulation of protein distribution deserves careful attention in the study of stress response. Indeed, recent work has shown that in the single cell eukaryote Saccharomyces cerevisiae more than half of the proteome radically changes its localization under different stress condition (Breker et al. 2013). By altering the spatial positioning of proteins, cells can change Electronic supplementary material The online version of this article

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The pathophysiology of neurodegenerative disease: Disturbing the balance between phase separation and irreversible aggregation

Webber

Lei

Wolozin

2020

Progress in Molecular Biology and Translational Science

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Imperfect asymmetry: The mechanism governing asymmetric partitioning of damaged cellular components during mitosis

Cited by 8 publications

References 87 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Imaging stress

The pathophysiology of neurodegenerative disease: Disturbing the balance between phase separation and irreversible aggregation

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