FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16^INK4a increase

Abstract

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Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin

“…In astrocytes, mHTT may up-regulate cytosolic DNA sensing pathways, raising the possibility that release of nucleic acids in the cytosol of astrocytes might be associated with HD pathogenesis, as recently validated for the release of mitochondrial RNA in the MSNs of Hdh mice ( Lee et al, 2020 ). The development of cellular senescence in human HD neural stem cells and MSNs ( Voisin et al, 2020 ) provides an additional level of validation for the central importance of the dynamics of stress response in HD. Geomic analysis provided detailed information on the nature and evolution of molecular response to HD in the mouse striatum mostly for Drd1 -MSNs (direct pathway striatal projection neurons) and astrocytes.…”

Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

“…FPR2 (a G protein-coupled receptor which mediates the inflammatory response) and p38 MAPK (a stress response protein) were both implicated in the senescence induction of NSCs [ 108 ]. These in vivo data were largely driven by the use of p16 antibody staining and SA β-gal, both of which are somewhat unreliable due to lack of specificity (as discussed in [ 110 ] and [ 15 ], respectively). Nonetheless, the suggestive data are compelling for further investigation.…”

“…Similarly, Voisin and colleagues [ 110 ] developed human iPSCs from a single patient with Huntington’s disease, a rare inherited neurodegenerative disease arising from mutations in the HTT gene. In this study, HTT CAG repeat-corrected (C116) cells from the same donors were used as a disease-free control.…”

“…Furthermore, they identified p16 and related genes as key mediators of senescence in Huntington’s disease NSCs and medium spiny neurons. Cells derived from the Huntington’s disease patient additionally showed decreased proliferation and elevated SA β-gal staining in vitro [ 110 ]. These results suggest that Huntington’s disease mutations may negatively impact NSC function and perhaps contribute to disease through senescence-mediated pathogenesis; however, senescence phenotypes will need to be confirmed in postmortem human brain tissue from patients with Huntington’s disease to validate these intriguing preclinical findings.…”

“…In addition, while many studies have relied heavily upon SA β-gal staining, few have adhered to proper protocols (see Section 2.4 .). Nonetheless, mechanistic studies utilizing brain NSCs are advancing our understanding of the molecular regulators of cellular senescence, including neurodegenerative disease-associated tau [ 109 ], Foxo3 [ 110 ], Myt1 [ 117 ], and lncRNA Hnscr [ 118 ]. Whether or not they are cell type specific remains unknown, but they highlight the utility and importance of evaluating senescence in brain cells.…”