Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging

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Science  16 Mar 2018:
Vol. 359, Issue 6381, pp. 1277-1283
DOI: 10.1126/science.aag3048

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Lysosomes keep neuronal stem cells young

An important consequence of aging is loss of regenerative capacity in stem cells, particularly those of the nervous system. Leeman et al. isolated quiescent and activated stem cells from mice and compared their transcriptomes. The findings emphasize the role of large lysosomes in quiescent neuronal stem cells in which aggregated proteins accumulate. Treatments that stimulated lysosomal function allowed aged quiescent stem cells to clear protein aggregates and restored the cells' ability to be activated. Such restoration of stem cell function might alleviate compromised proteostasis in aging.

Science, this issue p. 1277


In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.

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