Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies

Sun, Wenyan; Samimi, Hanie; Gamez, Maria; Zare, Habil; Frost, Bess

doi:10.1038/s41593-018-0194-1

Cited by 227 publications

(305 citation statements)

References 67 publications

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“…Prior studies have profiled brain gene expression in Tau transgenic animals, including in flies [31,32,52] and mouse models [21,23,41]; however, none to our knowledge have longitudinally assessed both transcripts and proteins in parallel. Our analyses provide a glimpse of the dynamic regulatory crosstalk between the brain transcriptome and proteome that respond to brain injury, as in tauopathy.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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BackgroundTau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau-versus agedependent changes. MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau WT ) or a mutation causing frontotemporal dementia (Tau R406W ). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. ResultsTau WT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. Tau R406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age-and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. BackgroundThe Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer's disease (AD) and other neurodegenerative tauopathies characterized by progressive cognitive and/or motor disability, including progressive supranuclear palsy (PSP), corticobasal degeneration, chronic traumatic encephalopathy, and certain forms of frontotemporal dementia (FTD) [1,2]. Rare mutations in the MAPT gene cause familial FTD, which is also characterized by prominent neurofibrillary tangle deposition [3][4][5]. Based on this genetic evidence, along with results from cellular and animal models [6,7], Tau is a critical mediator of age-related neurodegeneration and a causal link among this diverse group of neurologic disorders. While the precise mechanisms of Tauinduced neuronal injury remain incompletely defined, progressive synaptic dysfunction and neuronal loss likely arises from a cascade of cellular derangements, including oxidative-and immune-mediated injury, altered proteostasis, and aberrant transcription and translation [6,8].RNA-sequencing (RNA-seq) makes possible comprehensive gene expression profiling of postmortem human brain tissue in AD and o...

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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“…Additional studies have shown that expressed retrotransposon RNAs can also be toxic through aberrant recognition by innate immune components in Aicardi-Goutieres Syndrome (Crow and Manel, 2015). Other studies linked transposon activation in Alzheimer's disease with tau aggregation, and suggest these alterations accompany neuroinflammation and genomic instability (Guo et al, 2018;Sun et al, 2018). DNA damage and structural variants induced by transposition itself are a formal possibility, given the elevated levels of the fully competent LINE-1Hs retrotransposon, and evidence for active L1Hs transposition in human neurons (Evrony et al, 2016;Upton et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Tam

Rozhkov

Shaw

et al. 2019

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). Together these results demonstrate that at least three distinct molecular signatures contribute to ALS disease. While multiple dysregulated components and pathways comprising these clusters have previously been implicated in ALS pathogenesis, unbiased analysis of this large survey demonstrated that sporadic ALS patient tissues can be segregated into distinct molecular subsets.

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“…neurons has been proposed to contribute to age-dependent 337 neuronal decline in wildtype and disease models of Drosophila and (Li, e al., 2013; Guo et 338 al., 2018;Sun et al, 2018). Although the frequency of neural transposition is debated,339 expression is a prerequisite for movement.…”

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confidence: 99%

Transposon expression in theDrosophilabrain is driven by neighboring genes and diversifies the neural transcriptome

Treiber

Waddell

2019

Preprint

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Somatic transposition in neural tissue could contribute to neuropathology and individuality, but its prevalence is debated. We used single-cell mRNA sequencing to map transposon expression in the Drosophila midbrain. We found that neural transposon expression is driven by cellular genes. Every expressed transposon is resident in at least one cellular gene with a matching expression pattern. A new long-read RNA sequencing approach revealed that coexpression is a physical link in the form of abundant chimeric transposon-gene mRNAs. We identified 148 genes where transposons introduce cryptic splice sites into the nascent transcript and thereby produce many additional mRNAs. Some genes exclusively produce chimeric mRNAs with transposon sequence and on average transposon-gene chimeras account for 20% of the mRNAs produced from a given gene. Transposons therefore significantly expand the neural transcriptome. We propose that chimeric mRNAs produced by splicing into polymorphic transposons may contribute to functional differences between individual cells and animals.

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Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies

Cited by 227 publications

References 67 publications

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Transposon expression in theDrosophilabrain is driven by neighboring genes and diversifies the neural transcriptome

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