Lombardo, Michael V.

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Molecular Psychiatry (2021) 26:1432–1435https://doi.org/10.1038/s41380-020-0773-xCORRESPONDENCERibosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated inexpression in autismMichael V. Lombardo 1,2Received: 18 February 2020 / Revised: 21 April 2020 / Accepted: 29 April 2020 / Published online: 13 May 2020© The Author(s) 2020. This article is published with open accessTo the EditorIn a recent paper, Griesi-Oliveira et al. [1] identified a geneco-expression module in induced pluripotent stem cell(iPSC)-derived neural progenitor cells (NPCs) that isupregulated in expression in autism. The authors also showproteomic evidence to suggest that these earlier disruptionsin translation in NPCs may lead to dysregulation of geneexpression relevant to synaptic processes in neurons. Theseare valuable insights to contribute to the literature, parti-cularly because iPSC models can be a useful model of earlyprenatal periods of development. Griesi-Oliveira et al. [1]also attempted to assess how similar this kind of tran-scriptomic dysregulation is to previously reported studiesusing gene expression data in post-mortem cortical tissue.As the authors rightly note, the papers they utilized for thisanalysis [2, 3] did not themselves report any co-expressionmodules with differential module eigengene expression inmodules enriched for translation processes. However, in ourrecent paper [4], we re-analyzed data from these studies[2, 3] and indeed identified two consensus co-expressionmodules enriched in translation processes (M1 and M25)that were replicably upregulated in autism in both datasets.When we examine whether MNPC10-blue heavily overlapswith these translation-enriched modules, we indeed findhigh overlap with the translation-enriched M25 co-expression module (odds ratio (OR)= 15.52, p= 1.24e−14). Evidence from a later study by Gandal et al. [5] alsoshowed the presence of a co-expression module (geneM15)that is localized to the ribosome and enriched in excitatoryneuronal cell types. This autism-upregulated geneM15module from post-mortem cortical tissue highly overlapswith MNPC10-blue (OR= 19.10, p= 3.26e− 34) and theM25 module from our study (OR= 140.27, p= 1.09e−54). Nearly all of the overlapping genes in MNPC10-blue andLombardo et al.’s [4] M25 and Gandal et al.’s [5] geneM15are ribosomal protein genes (e.g., RPL and RPS). See Fig. 1for a graphical depiction of these gene sets and the overlap.The data and code that reproduces these results can befound here: https://github.com/mvlombardo/ipsc_translation. Thus, rather than there being no prior evidence ofupregulated translation co-expression modules in post-mortem cortical tissue, there is such evidence from multi-ple studies [4, 5], as well as evidence to support that manyof the same genes in MNPC10-blue are also those foundwithin those translation-enriched co-expression modulesfrom post-mortem cortical tissue.A second point of interest is that our prior paper makes astatement about how the cortical transcriptome is hier-archically disorganized in autism [4]. Evidence to supportthis comes from the result that eigengenes from upregulatedand downregulated co-expression modules are highly cor-related, with increases in the expression of translationmodules being associated with decreased expression ofsynaptic-enriched modules. In addition, dysregulated co-expression modules show a high degree of physical inter-actions at the protein level—that is, translation-enrichedmodules like M25 show a high level of protein–proteininteractions with proteins from genes from synaptic-enriched co-expression modules. Thus, the statement thatupregulated MNPC10-blue might be linked to dysregulationof neuronal co-expression modules in this iPSC dataset isindeed foreshadowed and predicted by our observations ofthis same kind of emergent disorganization across co-* Michael V. Lombardomichael.lombardo@iit.it1 Laboratory for Autism and Neurodevelopmental Disorders, Centerfor Neuroscience and Cognitive Systems @UniTn, Istituto Italianodi Tecnologia, Corso Bettini, 31, 38068 Rovereto, Italy2 Department of Psychiatry, Autism Research Centre, University ofCambridge, Cambridge, UK1234567890();,:1234567890();,:expression modules observed in post-mortem corticaltissue.Finally, it is worth discussing the potential importance ofthese upregulated co-expression modules enriched intranslation processes with respect to evidence already in theliterature. The authors have cited that protein synthesis is acellular process of interest in autism. Indeed, translationalcontrol has been of broad long-standing interest in autismresearch as many of the earliest known single gene muta-tions with high penetrance for autism are those that affecttranslational control (e.g., FMR1, TSC2, PTEN) [6]. Thesegenes, along with others (e.g., EIF4E, UBE3A, NF1,MECP2, SHANK3), all affect AKT-PI3K-mTOR signalingpathways [7–11] and these pathways are known to beaffected in idiopathic cases of autism [12, 13]. While theseare important prior starting points for talking about proteinsynthesis in autism, there is a missed opportunity here toexpand beyond this evidence. For example, the MNPC10-blue co-expression module has a large number of genescoding for 40S and 60S ribosomal subunits (RPL andRPS genes) and these genes are key members of our pre-viously reported M25-upregulated translation-enriched co-expression module [4] as well as the autism-upregulatedgeneM15 module from Gandal et al. [5]. These genes aswell as the ribosome cellular component itself are largelynot focused on in the literature. The evidence from ourpaper [4] and others [14], as well as this new evidence fromGriesi-Oliveira et al. [1] should underscore the idea thatM10NPC-M25 overlapM10NPC M25Lombardo et al., 2017Griesi-Oliveira et al.,geneM15Gandal et al., 2018Ribosomal ProteinsRibosomal ProteinsRibosomal ProteinsM10NPC-geneM15 overlapFig. 1 Graphs showing protein–protein interactions from STRING(https://string-db.org) for genes within co-expression modulesMNPC10-blue from Griesi-Oliveira et al. [1] (top left), M25 fromLombardo et al. [4] (top middle), and geneM15 from Gandal et al.[5] (top right). Ribosomal proteins are highlighted in red. In thebottom left are genes that overlap between MNPC10-blue and M25,while on the bottom right are genes that overlap between MNPC10-blueand geneM15.Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are. . . 1433future work should focus more heavily on this type oftranslation-relevant biology. Furthermore, such upregula-tion of translation-relevant biology (e.g., genes for riboso-mal proteins) are known to be similarly upregulated inmaternal immune activation [15] and in non-neural celltypes such as blood leukocytes from patients with autism[16, 17]. Finally, similar co-expression modules identifiedin blood leukocytes are associated with functional neuralphenotypes relevant to receptive speech processing in aut-ism with poor language outcome [18].These insights raise questions for how future work mightexpand on the relevance of upregulated ribosomal proteingenes in brain development in autism? Here I suggest acouple of routes that could be examined. First, the upre-gulated expression of ribosomal protein genes could suggestthat ribosome biogenesis is enhanced, and thus proteinsynthesis is also enhanced. Therefore, examination ofribosome biogenesis could be an important avenue of futurework in autism, particularly if enhanced ribosome biogen-esis affects specific cell types (e.g., excitatory neurons,radial glia). Second, enhanced protein synthesis—be itthrough enhanced ribosome biogenesis or other knownautism-associated mechanisms (e.g., FMR1, TSC2, PTEN,mTOR signaling)—could lead to enhanced cell prolifera-tion. It is also known that cell proliferation and proteinsynthesis are tightly linked [19], and in cancer research,many mechanisms relevant to suppressing or enhancing cellgrowth and proliferation affect ribosome biogenesis andprotein synthesis [20]. This route may be relevant forexamining molecular mechanisms that could underlieaccelerated early brain overgrowth in autism [11, 21] and/orsubtypes of patients with much larger brains [22]. Giventhe insights from Griesi-Oliveira et al. [1] for showing thisprocess is already upregulated in NPCs, this avenuecould be interesting from the standpoint that specific typesof progenitor cells (e.g., ventricular or outer radial glia)in very early fetal brain development are implicated inthe expansion of cortical surface area [23, 24]. Third,ribosomal proteins can have non-ribosomal functions, suchas involvement in the immune system [20]. These functionscan emerge because steps in ribosome biogenesis canbe disturbed (i.e. ribosomal stress) and lead to an accumu-lation of ribosome-free ribosomal proteins in the cell.Whether these extra-ribosome functions are a factor inautism is unknown, but this could be another route for howenhanced ribosomal proteins could potentially affect autisticpatients.In conclusion, the discoveries of Griesi-Oliveria et al. [1]are important and highlight the idea that upregulatedtranslation processes and their interaction with otherimportant biological processes taking place at the synapsebe prioritized as a fruitful area for future discoveries. Whiletranslational control is itself an area of much interest inautism [6–10], there is likely more to this topic than cur-rently understood and more emphasis could also be placedon the importance of ribosomal proteins.Compliance with ethical standardsConflict of interest The author declares no conflict of interest.Publisher’s note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, aslong as you give appropriate credit to the original author(s) and thesource, provide a link to the Creative Commons license, and indicate ifchanges were made. The images or other third party material in thisarticle are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is notincluded in the article’s Creative Commons license and your intendeduse is not permitted by statutory regulation or exceeds the permitteduse, you will need to obtain permission directly from the copyrightholder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.References1. Griesi-Oliveira K, Fogo MS, Pinto BGG, Alves AY, Suzuki AM,Morales AG, et al. Transcriptome of iPSC-derived neuronal cellsreveals a module of co-expressed genes consistently associatedwith autism spectrum disorder. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0669-9.2. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S,et al. Transcriptomic analysis of autistic brain reveals convergentmolecular pathology. Nature. 2011;474:380–4.3. Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J, et al.Transcriptome analysis reveals dysregulation of innate immuneresponse genes and neuronal activity-dependent genes in autism.Nat Commun. 2014;5:1–8.4. 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Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated in expression in autism

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Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated in expression in autism

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