Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

Minaya, Miguel; Mahali, Sidhartha; Iyer, Abhirami K.; Eteleeb, Abdallah M.; Martinez, Rita; Huang, Guangming; Budde, John; Temple, Sally; Nana, Alissa L.; Seeley, William W.; Spina, Salvatore; Grinberg, Lea T.; Harari, Oscar; Karch, Celeste M.

doi:10.3389/fmolb.2023.1051494

Cited by 10 publications

(29 citation statements)

References 144 publications

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“…LncRNAs can alter gene expression by cis or trans mechanisms. We found that the commonly differentially expressed lncRNAs were highly correlated with coding genes commonly differentially expressed in the presence of MAPT mutations (Minaya et al 2023). Gene enrichment analyses identified pathways related to Neurotrophin trk receptor signaling, Notch signaling, BDNF signaling, lipoprotein lipase activity, and axonal guidance.…”

Section: Discussionmentioning

confidence: 96%

“…Differential gene expression analyses comparing controls with PSP and AD brains were performed using a “Simple Model” that employs multi-variable linear regression analyses using normalized gene expression measures and corrected by sex, age-at-death, RNA integrity number (RIN), brain tissue source, and flowcell as covariates (Allen et al 2016). Transcriptomic data from the middle temporal gyrus of FTLD-tau patients with MAPT IVS10+16 and p.P301L mutation ( MAPT IVS10+16 n=2 and MAPT p.P301L n=1) and neuropathology free controls (n=3) were also analyzed (Minaya et al 2023). Differential expression analyses comparing FTLD-tau mutation carrier brains with controls was performed using DESeq2 (v.1.22.2) R package (Love, Huber, and Anders 2014) as previously described (Minaya et al 2023).…”

Section: Methodsmentioning

confidence: 99%

“…Transcriptomic data from the middle temporal gyrus of FTLD-tau patients with MAPT IVS10+16 and p.P301L mutation ( MAPT IVS10+16 n=2 and MAPT p.P301L n=1) and neuropathology free controls (n=3) were also analyzed (Minaya et al 2023). Differential expression analyses comparing FTLD-tau mutation carrier brains with controls was performed using DESeq2 (v.1.22.2) R package (Love, Huber, and Anders 2014) as previously described (Minaya et al 2023).…”

Section: Methodsmentioning

confidence: 99%

“…To begin to define the regulatory role of the 15 common lncRNAs, we evaluated the impact of these lncRNAs on coding gene expression. We have previously reported that these three classes of MAPT mutations are sufficient to drive altered gene expression of 275 protein coding genes (p<0.05; (Minaya et al 2023). LncRNAs can act in a cis or trans manner to inhibit or activate transcription of protein coding genes (Statello et al 2021).…”

Section: Mutant Tau-regulated Lncrnas Disrupt the Expression Of Codin...mentioning

confidence: 99%

“…Disruption of non-coding regulatory elements in the genome may have broad downstream effects that have yet to be fully explored in FTLD-tau (Simone et al 2021; Yan et al 2020). Stem cell modeling along with genome editing have revealed that MAPT mutations are sufficient to elicit a number of molecular events associated with synaptic function and proteostasis (Bowles et al 2021; Hernandez et al 2019; Jiang et al 2018; Mahali et al 2022; Minaya et al 2023). These studies have focused on understanding the effects of MAPT mutations on coding genes.…”

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNASNHG8drives stress granule formation in tauopathies

Bhagat

Minaya

Renganathan

et al. 2023

Preprint

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Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in theMAPTgene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream ofMAPTmutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying aMAPTp.P301L, IVS10+16, or p.R406W mutation, and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of theMAPTmutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the threeMAPTmutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs,SNHG8was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer’s disease brains. We show thatSNHG8interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tauin vitrois sufficient to reduceSNHG8expression and induce stress granule formation. RescuingSNHG8expression leads to reduced stress granule formation and reduced TIA1 levels, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Mutant Tau-regulated Lncrnas Disrupt the Expression Of Codin...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNASNHG8drives stress granule formation in tauopathies

Bhagat

Minaya

Renganathan

et al. 2023

Preprint

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A genetic and proteomic comparison of key AD biomarkers across tissues

Marsh,

Western,

Timsina

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONPlasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD.METHODEleven proteins associated with AD (α‐synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP‐25, TREM2, VILIP‐1, YKL‐40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome‐wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power.RESULTSEighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma.DISCUSSIONThe present results indicate that CSF is more informative than plasma for genetic studies in AD.Highlights The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration‐related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase‐3‐like protein 1 (YKL‐40) tend to show relatively strong inter‐tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.

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Long non-coding RNA SNHG8 drives stress granule formation in tauopathies

Bhagat,

Minaya,

Renganathan

et al. 2023

Mol Psychiatry

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Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer’s disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.

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Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

Cited by 10 publications

References 144 publications

Long non-coding RNASNHG8drives stress granule formation in tauopathies

Long non-coding RNASNHG8drives stress granule formation in tauopathies

A genetic and proteomic comparison of key AD biomarkers across tissues

Long non-coding RNA SNHG8 drives stress granule formation in tauopathies

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