Brain microRNAs dysregulation: Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer’s disease and related tauopathies

Bazrgar, Maryam; Khodabakhsh, Pariya; Mohagheghi, Fatemeh; Prudencio, Mercedes; Ahmadiani, Abolhassan

doi:10.1016/j.phrs.2020.104729

Cited by 22 publications

(16 citation statements)

References 117 publications

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“…In addition to this, changes in microRNA expression as demonstrated for miR-326-3p and miR-3547-3p can affect key splicing regulators like Srrm4. Comparatively, the role of miRNAs in the regulation of alternative splicing of tau was investigated in the brain, and their changes were shown to associate with the development of Alzheimer's disease [50]. One example is miR132, which directly targets the neuronal splicing factor PTBP2 (polypyrimidine tract-binding protein 2) [51].…”

Section: Discussionmentioning

confidence: 99%

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

Wilhelmi

Neumann²,

Jähnert

et al. 2021

IJMS

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Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.

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Section: Discussionmentioning

confidence: 99%

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

Wilhelmi

Neumann²,

Jähnert

et al. 2021

IJMS

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“…Taken together, these observations provide strong evidence that tau is a bone fide miRNA target that now awaits in vivo validation using gene editing technologies. Interestingly, the ratio between tau 3 ′ UTR isoforms seems to differ between healthy and AD brain (12,24). Whether this results in altered miRNA regulation requires further investigation.…”

Section: Perspective Article Evidence That Tau Is a Microrna Targetmentioning

confidence: 97%

“…As stated above, alternative splicing and phosphorylation are key elements of tau regulation and function. Nearly 15 miRNAs have been implicated so far in the indirect modulation of tau ( 8 , 25 ). These “tau modifier” genes are mostly kinases, and include Gsk-3β [miR-132 ( 26 ), miR-125b ( 27 ), miR-124 ( 28 ), miR-219 ( 29 , 30 ), miR-138 ( 31 )], Cdk5 [miR-125b ( 32 , 33 ), miR-26b ( 34 ), miR-195 ( 35 )], Erk [miR-125b ( 32 )], Itpkb [miR-132 ( 36 )], Fyn [miR-369 ( 37 ), miR-106b ( 38 )], and Rock1 [miR-146a ( 39 )].…”

Section: Perspective Articlementioning

confidence: 99%

Advances and Challenges in Understanding MicroRNA Function in Tauopathies: A Case Study of miR-132/212

et al. 2020

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“…Other miRNAs shared by AD and GBM are miRNAs-9, 106b, −124, −132 and 138, all related to Tau phosphorylation. In addition, miRNAs-9 and 132 were also linked to other Tau post-translational modifications, such as acetylation ( Bazrgar et al, 2020 ). In addition, miRNA-9, −124, −132 and −137, among others were related to Tau alternative splicing.…”

Section: Mirnas As Modulators Of Parkinson’s and Alzheimer’s Diseasesmentioning

confidence: 99%

Extracellular Vesicles Loaded miRNAs as Potential Modulators Shared Between Glioblastoma, and Parkinson’s and Alzheimer’s Diseases

Thomas

Florio

Perez-Castro

2020

Front. Cell. Neurosci.

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Glioblastoma (GBM) is the deadliest brain tumor. Its poor prognosis is due to cell heterogeneity, invasiveness, and high vascularization that impede an efficient therapeutic approach. In the past few years, several molecular links connecting GBM to neurodegenerative diseases (NDDs) were identified at preclinical and clinical level. In particular, giving the increasing critical role that epigenetic alterations play in both GBM and NDDs, we deeply analyzed the role of miRNAs, small non-coding RNAs acting epigenetic modulators in several key biological processes. Specific miRNAs, transported by extracellular vesicles (EVs), act as intercellular communication signals in both diseases. In this way, miRNA-loaded EVs modulate GBM tumorigenesis, as they spread oncogenic signaling within brain parenchyma, and control the aggregation of neurotoxic protein (Tau, Aβ-amyloid peptide, and α-synuclein) in NDDs. In this review, we highlight the most promising miRNAs linking GBM and NDDs playing a significant pathogenic role in both diseases.

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Brain microRNAs dysregulation: Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer’s disease and related tauopathies

Cited by 22 publications

References 117 publications

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

Advances and Challenges in Understanding MicroRNA Function in Tauopathies: A Case Study of miR-132/212

Extracellular Vesicles Loaded miRNAs as Potential Modulators Shared Between Glioblastoma, and Parkinson’s and Alzheimer’s Diseases

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