A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis

Lee, Eunbeol; Jung, Yeonjoo; Park, Yu Rim; Lim, Seongjoon; Choi, Youngjin; Lee, Se Young; Kim, Chan Hyuk; Mun, Ji Young; Chung, Won‐Suk

doi:10.1038/s43587-022-00257-1

Cited by 25 publications

(19 citation statements)

References 53 publications

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“…In this frame, the UPS and the autophagy-lysosomal pathway are crucial for controlling cellular proteostasis [ 9 ] and we focused on both pathways to understand how their impairment contributes to the pathology. Significant differences between WT and AD immortalized hippocampal astrocytes were observed, coherently with previous research on human and murine samples [ 3 , 15 , 64 ] and confirming the validity of these immortalized astrocytes.…”

Section: Discussionsupporting

confidence: 89%

Immortalized Alzheimer’s Disease Astrocytes: Characterization of Their Proteolytic Systems

et al. 2023

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Alzheimer’s disease (AD) is a progressive neurodegeneration with dysfunctions in both the ubiquitin–proteasome system (UPS) and autophagy. Astroglia participation in AD is an attractive topic of research, but molecular patterns are partially defined and available in vitro models have technical limitations. Immortalized astrocytes from the hippocampus of 3xTg-AD and wild-type mice (3Tg-iAstro and WT-iAstro, respectively) have been obtained as an attempt to overcome primary cell line limitations and this study aims at characterizing their proteolytic systems, focusing on UPS and autophagy. Both 26S and 20S proteasomal activities were downregulated in 3Tg-iAstro, in which a shift in catalytic subunits from constitutive 20S proteasome to immunoproteasome occurred, with consequences on immune functions. In fact, immunoproteasome is the specific complex in charge of clearing damaged proteins under inflammatory conditions. Parallelly, augmented expression and activity of the lysosomal cathepsin B, enhanced levels of lysosomal-associated membrane protein 1, beclin1, and LC3-II, together with an increased uptake of monodansylcadaverine in autophagic vacuoles, suggested autophagy activation in 3Tg-iAstro. The two proteolytic pathways were linked by p62 that accumulated in 3Tg-iAstro due to both increased synthesis and decreased degradation in the UPS defective astrocytes. Treatment with 4-phenylbutyric acid, a neuroprotective small chemical chaperone, partially restored proteasome and autophagy-mediated proteolysis in 3Tg-iAstro. Our data shed light on the impaired proteostasis in 3Tg-iAstro with proteasome inhibition and autophagic compensatory activation, providing additional validation of this AD in vitro model, and propose a new mechanism of action of 4-phenylbutyric acid in neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 89%

Immortalized Alzheimer’s Disease Astrocytes: Characterization of Their Proteolytic Systems

et al. 2023

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“…For example, while GSTP is mostly expressed in mature oligodendrocytes in the mouse brain, their expression is exclusive to neurons in the substantia nigra and controls neuronal sensitivity to MPTP-induced neurodegeneration (Smeyne et al, 2007). We and others have also shown that GSTM1 is enriched in astrocytes and controls astrocytemediated inflammatory changes (Sharma et al, 2015;Kano et al, 2019;Lee et al, 2022). Thus, emerging evidence supports for critical roles of GSTs in neuroinflammation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 72%

“…GSTM1 in astrocytes may also be involved in agingassociated changes in the brain and possibly aging-associated neurodegenerative diseases. A very recent study reported that a unique aging-associated astrocyte subtype in the hippocampus, exhibiting dysregulated autophagy and morphology, was enriched with GSTM1 expression (Lee et al, 2022). The study further showed that GSTM1 expression gradually increased in the hippocampus during aging.…”

Section: Discussionmentioning

confidence: 73%

Glutathione S-transferases Control astrocyte activation and neuronal health during neuroinflammation

Matoba

Dohi²,

Choi³

et al. 2023

Front. Mol. Biosci.

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Glutathione S-transferases (GST) are phase II detoxification enzymes of xenobiotic metabolism and readily expressed in the brain. Nevertheless, the current knowledge about their roles in the brain is limited. We have recently discovered that GSTM1 promotes the production of pro-inflammatory mediators by astrocytes and enhances microglial activation during acute brain inflammation. Here we report that GSTM1 significantly affects TNF-α-dependent transcriptional program in astrocytes and modulates neuronal activities and stress during brain inflammation. We have found that a reduced expression of GSTM1 in astrocytes downregulates the expression of pro-inflammatory genes while upregulating the expression of genes involved in interferon responses and fatty acid metabolism. Our data also revealed that GSTM1 reduction in astrocytes increased neuronal stress levels, attenuating neuronal activities during LPS-induced brain inflammation. Furthermore, we found that GSTM1 expression increased in the frontal cortex and hippocampus of aging mice. Thus, this study has further advanced our understanding of the role of Glutathione S-transferases in astrocytes during brain inflammation and paved the way for future studies to determine the critical role of GSTM1 in reactive astrocyte responses in inflammation and aging.

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“…We identified 8 clusters, among which we performed DE analysis (Supplementary table 2E). Based on expression of known markers we identified four clusters of GNPs (based on expression of ID1 , ID2 , ID3 , MEIS2 , ATOH1 , DCC and DCX ), two RL clusters (based on TMEM132D and CRABP1 expression, respectively) and one small glial cluster (based on SCRG1 and TSC22D expression (Aldinger et al, 2021; Lee et al, 2022) comprising 67 cells. Like day 7, we observed a small cluster of 55 cells that proved difficult to annotate that we designated Unannotated-2 (Un-2).…”

Section: Resultsmentioning

confidence: 99%

Directed differentiation of human hindbrain neuroepithelial stem cells recapitulates cerebellar granule neurogenesis

Dave

Chen

McCready

et al. 2023

Preprint

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Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain and modulate cerebellar output to the motor cortex. Dysregulation of CGN development underlies movement disorders and medulloblastomas. It is suspected that these disorders arise in progenitor states of the CGN lineage, for which human models are lacking. Here, we have differentiated human hindbrain neuroepithelial stem (hbNES) cells to CGNsin vitrousing soluble growth factors, recapitulating key progenitor states in the lineage. We show that hbNES cells are not lineage committed and retain rhombomere 1 (r1) regional identity. Upon differentiation, hbNES cells first transit through a rhombic lip (RL) progenitor state at day 7, demonstrating human specific sub-ventricular cell identities. This RL state is followed by an ATOH1+CGN progenitor state at day 14. By the end of a 56-day differentiation procedure, we obtain mature neurons expressing CGN markers GABAAa6 and vGLUT2. These neurons generate spontaneous and evoked action potentials. A small fraction of endpoint neurons were unipolar brush cells (UBC). We noted maintenance of a RL population throughout differentiation, as is consistent with human development. We show that sonic hedgehog (SHH) promotes γ-aminobutyric acid (GABA)-ergic lineage specification and is a positive regulator of CGN progenitor proliferation. Interestingly, we observed that functional neuronal maturation is impaired by either elevated or absent SHH signaling. Impaired maturation under high SHH levels represents the potential of our system to model cerebellar tumorigenesis. Further, our data suggest a potential pro-differentiation role of SHH within a certain concentration range. Our work is, to our knowledge, the first detailed temporal characterization of the complete human CGN lineagein vitro. Our system recapitulates developmentally relevant progenitor states and is a new tool to model this specific cerebellar lineage, and how it may be disrupted to cause human disease.

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A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis

Cited by 25 publications

References 53 publications

Immortalized Alzheimer’s Disease Astrocytes: Characterization of Their Proteolytic Systems

Immortalized Alzheimer’s Disease Astrocytes: Characterization of Their Proteolytic Systems

Glutathione S-transferases Control astrocyte activation and neuronal health during neuroinflammation

Directed differentiation of human hindbrain neuroepithelial stem cells recapitulates cerebellar granule neurogenesis

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