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Glasauer SM, Goderie SK, Rauch JN, Guzman E, Audouard M, Bertucci T, Joy S, Rommelfanger E, Luna G, Keane-Rivera E, Lotz S, Borden S, Armando AM, Quehenberger O, Temple S, Kosik KS. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Reports. 2022 Sep 13;17(9):2127-2140. Epub 2022 Aug 18 PubMed.
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Boston University School of Medicine
Studies on tauopathy, especially those of MAPT mutations, have mainly focused on neurons, since MAPT is expressed in these cells and is known to dysregulate them. This study, using human organoids composed of various neurons and glia, comes from an interesting angle. The astrocytes express both mutant and control MAPT in the context of a brain environment that includes multiple cell types, and the findings suggest both a cell-autonomous effect of MAPT in astrocytes and a non-cell-autonomous effect in mutant astrocytes driven from mutant MAPT in neurons. Regardless, they report that a major defect in tauopathy mutants in astrocytes was upregulation of cholesterol biosynthesis, which we have reported as the major dysregulation caused by APOE4 in glia in AD and in many other neurodegenerative diseases (TCW et al., 2022). The findings suggest a potential therapeutic target for early intervention.
References:
Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25. PubMed. BioRxiv.
View all comments by Julia TCWDartmouth Medical School
Dartmouth Medical School
We read the work of Glasauer et al. with great interest. The authors performed scRNA-Seq, immunohistochemical staining, and lipidomic analyses in human organoids. They elegantly demonstrated that mutant taus upregulated the expressions of several enzymes in the cholesterol biosynthetic pathway, including HMG-CoA synthase and HMG-CoA reductase, in astrocytes. Thus, upregulation in cholesterol biosynthesis in astrocytes is one of the significant responses to the pathogenic cascade initiated by mutant forms of tau.
The authors found that ACAT2 expression in astrocytes is also upregulated. On page 2131, they wrote, "ACAT2, encoding an enzyme converting cholesterol to its storage form cholesteryl esters." We feel it is important to point out that in this work, ACAT2 does not stand for a cholesterol storage enzyme; instead, it stands for acetyl-CoA C-acetyltransferase, which is the first enzyme in the cholesterol biosynthetic pathway. As an off-topic comment: ACAT1 stands for a distinct acetyl-CoA acetyltransferase located in the mitochondria and plays a crucial role in ketogenesis.
The enzyme responsible for converting cholesterol to its storage form is known as "acyl-CoA: cholesterol acyltransferase." For many years, it has been abbreviated as ACAT. There are two ACATs. ACAT1 was identified in 1993; ACAT2 was identified in 1998. To avoid confusion with acetyl-CoA acetyltransferases, the HUGO Gene Nomenclature Committee recommended that acyl-CoA: cholesterol acyltransferase be renamed sterol O-acyltransferases and abbreviated as SOATs. In recent years, these enzymes are often referred to as ACATs/SOATs.
Both ACAT1/SOAT1 and ACAT2/SOAT2 are multi-span membrane proteins located at the endoplasmic reticulum. Unlike enzymes in the cholesterol biosynthetic pathway, neither ACAT1/SOAT1 nor ACAT2/SOAT2 is transcriptionally regulated by the master transcription factor SREBP2. Instead, each enzyme is allosterically activated by sterols, including cholesterol and oxysterols; this mechanism enables ACATs/SOATs to respond rapidly to changes in cellular sterol levels. ACATs/SOATs are targeted to treat several human diseases, including cardiovascular disease, neurodegenerative diseases, and certain forms of cancer. A recent review on ACATs/SOATs is available (Rogers et al., 2015).
—Michael Duong of University of Pennsylvania School of Medicine co-authored this comment.
References:
Rogers MA, Liu J, Song BL, Li BL, Chang CC, Chang TY. Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol. 2015 Jul;151:102-7. Epub 2014 Sep 12 PubMed.
University of California, Santa Barbara
University of California, Santa Barbara
We would like to thank Drs. Ta-Yuan Chang and Catherine Chang, and Michael Duong for their interest in our paper and their comment.
The identifier ACAT has been used ambiguously in the literature: acyl-CoA: cholesterol acyltransferases (catalyzing esterification of cholesterol) and acetyl-CoA acetyltransferases (catalyzing the conversion of two units of acetyl-CoA to acetoacetyl-CoA) have both been referred to as ACATs, even in the recent literature.
The comment’s authors correctly state that the gene symbol ACAT2, which we refer to in our paper, encodes an acetyl-CoA acetyltransferase according to current gene name convention.
This does not change the story of our paper and will only change two sentences in the results section.
Specifically, currently we write:
15 of these genes encode enzymes of the cholesterol synthesis pathway, including its rate limiting enzyme HMGCR (Fig. 3A). Also ACAT2, encoding an enzyme converting cholesterol to its storage form cholesteryl esters, STARD4, encoding an intracellular cholesterol transporter, LDLR, encoding an important receptor for cholesterol uptake, and SREBF2, encoding a transcriptional activator of cholesterol biosynthesis enzymes, were significantly upregulated (Figure 3A).
Instead, it should say:
16 of these genes encode enzymes of the cholesterol synthesis pathway, including its rate limiting enzyme HMGCR (Fig. 3A). Also STARD4, encoding an intracellular cholesterol transporter, LDLR, encoding an important receptor for cholesterol uptake, and SREBF2, encoding a transcriptional activator of cholesterol biosynthesis enzymes, were significantly upregulated (Figure 3A).
Amsterdam UMC, loc. VUmc
Maastricht University; VU University Medical Centre
In this work, Glasauer and colleagues investigated RNA expression differences of pyramidal neurons and astrocytes from organoids with a MAPT mutation compared to their isogenic controls. Most differences were found in neurons, where MAPT also has the highest expression. Sixty genes were downregulated and associated with glucose metabolism, 80 genes were upregulated and associated with mitochondrial function.
Glasauer and colleagues next compared astrocytes between MAPT mutation and control organoids, and observed upregulated genes associated with cholesterol metabolism, including SREBF2. SREBF2 is a transcription factor that regulates cholesterol metabolism. Another study recently also identified SREBF2 to be implicated in cholesterol metabolism alterations that were associated with the APOE e4 genotype (TCW et al., 2022). SREBF2 can be activated by endoplasmic reticulum stress, and can subsequently disrupt lipid metabolism (Colgan et al., 2007).
In Alzheimer’s disease and other tauopathies, aggregation of tau can cause endoplasmic reticulum stress (Hoozemans and Scheper, 2012). It would be interesting to further study the role of phosphorylated tau in endoplasmic reticulum stress and cholesterol metabolism in the MAPT organoids.
References:
Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25. PubMed. BioRxiv.
Colgan SM, Tang D, Werstuck GH, Austin RC. Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2. Int J Biochem Cell Biol. 2007;39(10):1843-51. Epub 2007 May 16 PubMed.
Hoozemans JJ, Scheper W. Endoplasmic reticulum: The unfolded protein response is tangled in neurodegeneration. Int J Biochem Cell Biol. 2012 Aug;44(8):1295-8. PubMed.
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