. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nat Med. 2019 Jan;25(1):152-164. Epub 2018 Dec 3 PubMed.

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  1. There is a pernicious trend in scientific publishing favoring unwieldy papers that appear to escape critical evaluation because their scientific merit can no longer be adequately assessed by reviewers. This paper is a standout, although it ironically also summarizes a Herculean body of work. It manages to stay focused on its objective to identify gene expression modules that may not only be associated with disease but have a higher chance to be causally linked to it by their enrichment in GWAS hits.

    Much of the study focuses on two neurodegeneration-associated gene-expression modules that emerged from deep RNA-seq analyses of four brain tissues obtained at two ages from mice expressing P301S tau on three distinct genomic backgrounds. Whereas the first module was associated with neurons and enriched in synaptic pathway genes (NAS), the other could be linked to microglial, astrocytes, and endothelial cells and fittingly was enriched in immune and inflammatory genes (NAI).

    Intriguingly, consistent gene expression changes within these modules were not only preserved in datasets from additional mouse models harboring pathological tau mutations but also in transgenic mice expressing distinct AD and FTD risk mutations, as well as the cortices of tau-negative and tau-positive FTD patients.

    Although the above suggests broad involvement of NAS and NAI modules in a variety of dementias, GWAS hits from AD mapped primarily to the NAI gene network and PSP/FTD genes were enriched in the NAS gene network, respectively. Thus, the data are consistent with an interpretation whereby there is cross-talk between these modules leading to convergent downstream etiology, but that the upstream causal pathways are distinct in these dementias.

    Noticing a strong inverse correlation between the expression of miR-203 and NAS gene products, the authors explored if this microRNA might be a driver that suppresses the expression of genes within this module. This turned out to be the case.

    Impressively, the study did not stop there but explored public data in the Connectivity Map (CMAP) database, which takes stock of how cell lines respond to drugs with gene-expression changes, for a compound that may revert the NAS and NAI module changes. A histone deacetylase inhibitor (Scriptaid), the top-scoring CMAP hit, then could be shown to reverse the death caused by miR-203 overexpression in a neuronal cell model.

    As with any good study, this work is no exception in that it raised many more questions than it could answer. Paramount among them loom how exactly histone deacetylases are linked to the NAS and NAI gene expression modules, and whether their inhibition can revert cell death in vivo. Dissecting the molecular underpinnings of their action may not be trivial, because both histone deacetylases and microRNAs typically have relatively low target specificity. However, the fact that the NAS module and its disease-relationship was also preserved in iPSC from human FTD patients carrying GRN mutations suggests that the latter might provide a suitable paradigm for follow-on investigations into the regulation of this module.

    The study should serve as a useful template for the application of integrated systems biology to other diseases. It makes for a refreshing read that I plan to recommend to students going forward.

    View all comments by Gerold Schmitt-Ulms
  2. This report on evolutionarily conserved gene networks mediating tau-related neurodegeneration by the group of Daniel Geschwind represents a very thorough and systematic study employing integrative co-expression network analyses in an impressive series of mouse and human datasets.

    By delving into the transcriptomic changes inferred by genetic background in conjunction to tau-induced neuropathology, the study adds to our realization of the significance of the genetic makeup for neurodegenerative disease progression. At the same time it emphasizes the usefulness of animal models for identifying possible disease-modifying molecular factors.

    The authors very elegantly dissect disease-specific transcriptional signatures that are region-, age-, or genetic background-directed and thereafter construct unique co-expression gene networks. Interestingly, the analyses converge into two modules that seem to be independent of genetic background and species; one associated with the neuronal/synaptic response and one with the immune response during tau-pathology progression.

    Even though this type of study cannot generally infer causality, the authors do a great job in further experimentally validating their findings and confirming the significance of microRNA regulators in neurodegeneration. Their observation that divergent genetic backgrounds in both mice and humans can lead to similar transcriptional responses that possibly associate with core pathological drivers or modifiers of tauopathies is one of the particularly exciting findings of this study. Moreover, that certain transcriptional modules consistently anti-correlated with disease progression may shed light onto novel approaches to harness endogenous neuroprotection mechanisms.

    Inevitably, the data also raise questions. Despite the depth and breadth of analysis, this work remains a bulk approach to brain transcriptomics. In light of recent reports on the many distinct, transcriptionally defined, microglial subtypes that seem to be differentially affected by brain pathology or aging, analyzing modules that relate to a pool of different cell types, like for instance microglia, astrocytes, and endothelia, precludes the ability to isolate the contribution of individual cell types to distinct forms of neurodegeneration.

    Similarly, limitations regarding network metrics may hinder the ability to unveil biological dynamics at the single-gene level. On the other side of the same spectrum, differential module enrichment for GWAS genes in AD (risk genes were enriched in the immune response module) compared to FTD and PSP (risk genes were enriched in the synaptic module), is a key observation derived from network-based analysis, and again underscores the hypothesis that genetic risk for AD is linked to an Aβ-, and not tau-induced immune response (Salih  et al., 2018; Sierksma et al., 2019; Felsky et al., 2019). 

    Lastly, it would have been of additional interest had the authors identified modules differentially regulated between human patient brain and animal disease models, as this would provide pivotal knowledge regarding the much-debated issue of the translational gap. In all, this study adds significant insights into disease mechanisms, possible dynamic network biomarkers, and novel disease-modifying strategies, and provides a wealth of information for interested researchers to further explore.

    References:

    . Genetic variability in response to Aβ deposition influences Alzheimer's risk. BioRxiv, October 8, 2018.

    . Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology. bioRxiv. January 16, 2019.

    . Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat Commun. 2019 Jan 24;10(1):409. PubMed.

    View all comments by Annerieke Sierksma
  3. This elegant and thoroughly planned work allows us to appreciate a potential molecular cascade that possibly normalizes downstream processes of a spectrum of neurodegenerative conditions including AD, FTD, and PSP. This comprehensive study uses animal and human models, computational methods, and experimental validation to support results and interpretation.

    The approach is quite state of the art. A major strength here is that systems biology approaches prove their affordability to the study of complex disorders by representing a step forward from the classic one-gene-at-a-time, reductionist approach. The current study indicates a conserved change in expression patterns of genes involved in synaptic and inflammatory processes as a communal feature in specific cell sub-populations in brain areas topologically relevant to neurodegenerative diseases such as AD, FTD and PSP.

    It also indicates that aberrant expression patterns appear to happen downstream of pathology. They are thus a consequence rather than a cause of the degenerative process, almost independent from the putative genetic cause or risk factors. This could be relevant in that it indicates that possibly some of the neurodegenerative processes across neurological conditions are the same, therefore effective therapeutic measures could target multiple different neurological conditions.

    All the more, this work highlights potential drug targets, already existing tool compounds and their effect on a signature of degeneration. This work is also important in that it validates previous, purely computational, work that particularly highlighted a potential functionally relevant role for acetylases (e.g., EP300—see also Dec 2018 conference news) or other targets (e.g., ELAVL proteins) in the pathogenesis FTD (Ferrari et al., 2016; Ferrari et al., 2017). 

    This study provides a great deal of new and useful insight into neurodegeneration processes in FTD, especially suggesting where and how disease progression might be halted or slowed. Yet, it is not fully able to explain causality; it rather highlights conserved and convergent subcellular events as a signature of an already initiated and irreversible degenerative process. It would be thus warranted to discriminate whether these processes are a cause or a consequence, maybe by modulating them at early stage in mouse models, before brain damage signatures occur.

    Another point to consider is that the current study has used a number of different and variable models to study disease. The authors have done a superlative job minimizing most confounding variables, yet possibly, in the future, multi-omics data integration approaches generated from the same sample sources might promise to be even more informative for human disease.

    Another point to consider might be that of verifying whether other micro-RNAs, in addition to miR-203, appear to modulate any of the edges of the candidate modules? Finally, if the two disease modules highlighted here are shared across different disorders AD, FTD, ALS, and PSP, and different genetic models of any of these disorders exist, how do we account for the phenotypic differences between these disorders? In other words, do other molecular signatures contribute to disease pathogenesis, as well, and are they exclusive to FTD (with or without tau pathology, or with or without GRN mutations), AD, and PSP, etc.? How do we experimentally discriminate those?

    References:

    . Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis. Mol Neurodegener. 2016 Feb 24;11:21. PubMed.

    . Weighted Protein Interaction Network Analysis of Frontotemporal Dementia. J Proteome Res. 2017 Feb 3;16(2):999-1013. Epub 2017 Jan 12 PubMed.

    View all comments by Raffaele Ferrari
  4. This is an exciting advance that uses systems biology and in vivo validation to generate mechanistic insight into the causes of neurodegenerative diseases including FTD and AD. Although autosomal-dominant mutations in MAPT, GRN, and C9ORF72 are frequent causes of FTD, it is still a mystery how these mutations precisely lead to neuronal dysfunction and ultimately degeneration. Moreover, current animal models of FTD and AD do not fully recapitulate the human condition, which may partially explain the difficulty of identifying efficacious drugs in clinical trials for multiple neurodegenerative diseases.

    This work led by Vivek Swarup in Dan Geschwind’s lab at UCLA attempts to overcome these challenges by incorporating network analysis of transcriptomic and proteomic data from mouse models of AD/FTD and human brain FTD tissue. This approach identified modules or groups of synaptic-associated genes that decreased or inflammatory-associated genes that increased across disease models, and importantly also in human FTD. A key microRNA, miR-203, was identified that appears critical for synaptic dysfunction and neuronal death in vitro and in vivo. Subsequently, small-molecule histone deacetylase inhibitors were identified that could rescue the disease-associated changes in synaptic and inflammatory genes.

    Taken together, this herculean effort suggests this type of systems-level approach can identify important pathogenic pathways in neurodegeneration that may be targetable by antisense oligonucleotides or small molecules. Much work remains, but it will be exciting to understand how miR-203 and associated pathways are involved in neurodegeneration and if they can be targeted effectively as therapeutic targets in FTD, AD, and related dementias.

    View all comments by Thomas Kukar

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