The aggregation and inheritance of damaged proteins determines cell fate during mitosis

Bufalino, Mary Rose; Kooy, Derek van der

doi:10.4161/cc.28106

Cited by 12 publications

(7 citation statements)

References 33 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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“…Cells can degrade damaged components with high efficiency via the Ubiquitin-Proteasome System (UPS) and autophagy 52 . Alternatively, dividing cells can partition damaged components into one of the daughter cells during mitosis, thus generating one lineage that is pristine and one that will accumulate damage 53 . Both rejuvenation systems have been observed in developing organisms.…”

Section: Discussionmentioning

confidence: 99%

Vimentin protects differentiating stem cells from stress

Pattabiraman

Azad

Amen

et al. 2020

Sci Rep

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Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.

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“…It has been reported that neural stem cells expressing a polyQ expansion protein suffer from impaired lineage restriction, reduced proliferative potential, and enhanced late-stage self-renewal (52), suggesting that polyQ pathology begins very early in the development of neural cells. Cell models expressing aggregation-prone polyQ proteins also experience problems with cell division, such as cell cycle arrest (51) and decreased proliferation (53). Furthermore, neuroimaging has shown that prodromal Huntington disease males have a smaller intracranial volume than controls, suggesting abnormal development in brain tissues expressing mutant Htt (54).…”

Section: Discussionmentioning

confidence: 99%

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Lü

Boschetti

Tunnacliffe

2015

Journal of Biological Chemistry

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Background:The formation of juxtanuclear aggresomes from aggregation-prone proteins is widely believed to be protective to cells. Results: Cell lines containing aggresomes suffer from DNA double-strand breaks, cell cycle arrest, mitotic defects, and apoptosis. Conclusion: Long term accumulation of aggresomes has detrimental effects on nuclear function in cells. Significance: This study provides the first evidence that aggresomes can cause significant cellular dysfunction in dividing cells.

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The aggregation and inheritance of damaged proteins determines cell fate during mitosis

Cited by 12 publications

References 33 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

Vimentin protects differentiating stem cells from stress

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

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