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Vimentin Helps to Keep Proteins in Balance in Neural Stem Cells

Review of “Vimentin Coordinates Protein Turnover at the Aggresome during Neural Stem Cell Quiescence Exit” from Cell Stem Cell by Stuart P. Atkinson

In their recent Cell Stem Cell article [1], researchers led by Darcie L. Moore (University of Wisconsin-Madison, USA) sought to discover if neural stem cells (NSCs) maintain proteostasis, and hence normal function, through the aggresome [2, 3] – a “hot-spot” of misfolded or damaged proteins surrounded by a cage composed of a type III intermediate filament called vimentin [4] present at the centrosome. A failure to balance the synthesis and degradation of proteins due to disease or during normal aging can lead to stem cell dysfunction, which, in the case of NSCs, includes the decreased ability to exit quiescence and the loss of neurogenic abilities [5-7]. The authors sought to explore the complex responses associated with increases in damaged/aggregated proteins in NSCs to highlight mechanisms that could be targeted to enhance adult neurogenesis.

Through the tagging of vimentin with a fluorophore, Morrow et al. found that adult hippocampal NSCs employ the aggresome to clear the high levels of polyubiquitinated or aggregated proteins that signal the loss of proteostasis. Furthermore, they described how the surrounding vimentin cage functioned as a spatial coordinator, ensuring the localization of the proteasome, a multi-subunit protein complex that processes polyubiquitinated proteins for degradation, to the aggresome. Of note, the authors also discovered that quiescent NSCs upregulate vimentin protein expression and utilize aggresomes during their exit from quiescence, a process required for ongoing neurogenesis; however, NSCs lacking vimentin display a reduced capacity to exit quiescence, thereby linking the accumulation of damaged proteins to the inhibition of neurogenesis.

Finally, the authors sought to corroborate their in vitro data by searching for clues to the existence of this mechanism in the mouse brain; excitingly, through the study of brain slices, the team found ample evidence that NSCs utilize aggresomes during the exit from quiescence in vivo. Furthermore, they also established that NSCs in the brains of mice lacking vimentin suffer from a decreased ability to exit quiescence in vivo and display an early age-dependent decline in proliferation and neurogenesis.

Overall, the authors provide ample evidence for a significant role for vimentin, aggresome formation, and the removal of damaged proteins with the help of the proteasome to the activation of quiescent NSCs and neurogenesis. These findings may contribute to the development of new strategies to increase neurogenesis after brain injuries, and as protein aggregation can occur in neurodegenerative diseases such as Alzheimer’s Disease, the study of vimentin and the aggresome may provide for the development of enhanced therapeutic strategies.

For more on neural stem cells, adult neurogenesis, and the need to keep your proteins in balance, stay tuned to the Stem Cells Portal!

References

  1. Morrow CS, Porter TJ, Xu N, et al., Vimentin Coordinates Protein Turnover at the Aggresome during Neural Stem Cell Quiescence Exit. Cell Stem Cell 2020;26:558-568.e9.
  2. Ogrodnik M, Salmonowicz H, Brown R, et al., Dynamic JUNQ Inclusion Bodies are Asymmetrically Inherited in Mammalian Cell Lines Through the Asymmetric Partitioning of Vimentin. Proceedings of the National Academy of Sciences 2014;111:8049.
  3. Johnston JA, Ward CL, and Kopito RR, Aggresomes: A Cellular Response to Misfolded Proteins. Journal of Cell Biology 1998;143:1883-1898.
  4. Moore DL, Pilz GA, Araúzo-Bravo MJ, et al., A Mechanism for the Segregation of Age in Mammalian Neural Stem Cells. Science 2015;349:1334.
  5. López-Otín C, Blasco MA, Partridge L, et al., The Hallmarks of Aging. Cell 2013;153:1194-1217.
  6. Audesse AJ, Dhakal S, Hassell L-A, et al., FOXO3 Directly Regulates an Autophagy Network to Functionally Regulate Proteostasis in Adult Neural Stem Cells. PLOS Genetics 2019;15:e1008097.
  7. Rodriguez-Fernandez IA, Qi Y, and Jasper H, Loss of a Proteostatic Checkpoint in Intestinal Stem Cells Contributes to Age-related Epithelial Dysfunction. Nature Communications 2019;10:1050.