Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Wu, Timothy; Deger, Jennifer; Ye, Hui; Guo, Caiwei; Dhindsa, Justin; Pekarek, Brandon; Al‐Ouran, Rami; Liu, Zhandong; Al‐Ramahi, Ismael; Botas, Juan; Shulman, James L.

doi:10.7554/elife.85251

Cited by 5 publications

(2 citation statements)

References 90 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S6 ). These findings are consistent with prior single-cell sequencing studies in flies overexpressing mutant human TAU ( Praschberger et al 2023 ; Wu et al 2023 ). We observed regulation of both common and distinct biological pathways when comparing differentially expressed genes across cell subtypes.…”

Section: Discussionsupporting

confidence: 91%

Transcriptional programs mediating neuronal toxicity and altered glial–neuronal signaling in aDrosophilaknock-in tauopathy model

Bukhari,

Nithianandam,

Battaglia

et al. 2024

Genome Res.

View full text Add to dashboard Cite

Missense mutations in the gene encoding the microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human tau in experimental model organisms, includingDrosophila, have been described. These models replicate key features of the human disease, but do not faithfully recreate the genetic context of the human disorder. Here we use CRISPR-Cas mediated gene editing to model frontotemporal dementia caused by the tau P301L mutation by creating the orthologous mutation, P251L, in the endogenousDrosophilataugene. Flies heterozygous or homozygous for tau P251L display age-dependent neurodegeneration, metabolic defects, and accumulate DNA damage in affected neurons. To understand the molecular events promoting neuronal dysfunction and death in knock-in flies we performed single-cell RNA sequencing on approximately 130,000 cells from brains of tau P251L mutant and control flies. We found that expression of disease-associated mutant tau altered gene expression cell autonomously in all neuronal cell types identified. Gene expression was also altered in glial cells, suggestive of non-cell autonomous regulation. Cell signaling pathways, including glial-neuronal signaling, were broadly dysregulated as were brain region and cell type-specific protein interaction networks and gene regulatory programs. In summary, we present here a genetic model of tauopathy, which faithfully recapitulates the genetic context and phenotypic features of the human disease and use the results of comprehensive single cell sequencing analysis to outline pathways of neurotoxicity and highlight the potential role of non-cell autonomous changes in glia.

show abstract

Section: Discussionsupporting

confidence: 91%

Transcriptional programs mediating neuronal toxicity and altered glial–neuronal signaling in aDrosophilaknock-in tauopathy model

Bukhari,

Nithianandam,

Battaglia

et al. 2024

Genome Res.

View full text Add to dashboard Cite

show abstract

“…Studying cell vulnerability in AD is important to understand disease progression, reveal biomarkers, and identify therapeutic targets. snRNA-seq serves as an ideal method to study cell vulnerability and several recent studies have employed snRNA-seq in different AD models and human patients (Lau et al, 2020; Mathys et al, 2023; Sziraki et al, 2023; Wang et al, 2024; Wu et al, 2023). Out of necessity, most of these studies have focused on a specific brain region and identified specific cell types that are selectively vulnerable.…”

Section: Discussionmentioning

confidence: 99%

Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer’s Disease fly models

Park,

Lu,

Jackson

et al. 2024

Preprint

View full text Add to dashboard Cite

Peripheral tissues become disrupted in Alzheimer's Disease (AD). However, a comprehensive understanding of how the expression of AD-associated toxic proteins, Aβ42 and Tau, in neurons impacts the periphery is lacking. Using Drosophila, a prime model organism for studying aging and neurodegeneration, we generated the Alzheimer's Disease Fly Cell Atlas (AD-FCA): whole-organism single-nucleus transcriptomes of 219 cell types from adult flies neuronally expressing human Aβ42 or Tau. In-depth analyses and functional data reveal impacts on peripheral sensory neurons by Aβ42 and on various non-neuronal peripheral tissues by Tau, including the gut, fat body, and reproductive system. This novel AD atlas provides valuable insights into potential biomarkers and the intricate interplay between the nervous system and peripheral tissues in response to AD-associated proteins.

show abstract

Rel governs loser elimination during stem cell competition in the Drosophila testis

Hof-Michel,

Cigoja,

Huhn

et al. 2024

European Journal of Cell Biology

View full text Add to dashboard Cite

Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Cited by 5 publications

References 90 publications

Transcriptional programs mediating neuronal toxicity and altered glial–neuronal signaling in aDrosophilaknock-in tauopathy model

Transcriptional programs mediating neuronal toxicity and altered glial–neuronal signaling in aDrosophilaknock-in tauopathy model

Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer’s Disease fly models

Rel governs loser elimination during stem cell competition in the Drosophila testis

Contact Info

Product

Resources

About