Findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.
Abstract
Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimer’s disease and Parkinson’s disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.
A mechanism wherein SChLAP1 modulates AR signaling to promote PCa growth and progression is suggested, suggesting its molecular mechanism and potential to be used as a therapeutic target or biomarker.
Astrocytic upregulation of HSP90AA1 is associated with altered synapse-related intercellular communication patterns in the PD substantia nigra, potentially involving a predicted TP53 associated regulatory component.
Yiyuan Xu, Yanfeng Shi, Yan Li et al.· International Journal of Mol...· 0 citations
A transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD is provided, and potential upstream therapeutic targets are revealed, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways.
Dysregulation of target genes of nonsense-mediated decay (NMD) in the brain remains sparsely known in tauopathies. PS19 transgenic mice expressing human mutant P301S tau were evaluated for levels of lncRNA Gas5, a target of NMD. The results show Gas5 decreased in the brains of PS19 mice as they aged. We evaluated the consequences of blocking the NMD-mediated turnover of Gas5 using a small molecule administered intranasally to PS19 mice. The results show NPC86 disassociated Upf1 and Gas5, thereby hindering NMD. NPC86 treatment increased Gas5 levels in the cortex of male PS19 mice concurrent with a highly significant decrease in pTau S214 and neuroinflammatory genes while increasing insulin signaling. Consequently, digital spatial profiling identified Gas5-regulated genes and pathways. NPC86 treatment enhanced neuronal homeostasis, synaptic vesicle transport and mitochondrial function and downregulated neuroinflammatory pathways. The nodal genes in Parkinson’s signaling pathway, the multiple sclerosis signaling pathway, the Gα(s) signaling pathway, the neuroinflammation signaling pathway, and the interferon gamma signaling pathway were decreased in response to NPC86. The study demonstrates the potential of selectively stabilizing NMD-target lncRNA Gas5 levels to alleviate early neurodegenerative pathology in tauopathy.
Meredith Krause-Hauch, Bangmei Wang, Rekha S. Patel et al.· International Journal of Mol...· 0 citations
Neurodegenerative diseases (NDs) are characterized by the progressive deterioration of cognitive and motor functions. In this context, glial cell-mediated neuroinflammation is recognized as a key driver of disease progression. Long non-coding RNAs (lncRNAs) have emerged as key epigenetic regulators that modulate gene expression and inflammatory signaling pathways in this context. Due to their high cell-type specificity and dynamic regulation, lncRNAs are promising diagnostic biomarkers and therapeutic targets for NDs. The balance between the neuroprotective and proinflammatory functions of glial cells plays a crucial role in ND progression. LncRNAs act as multifunctional modulators of glial activity, influencing neuroinflammatory responses, astrocyte and microglia dysfunction, and the clearance of toxic protein aggregates. Several lncRNAs, including RMST, MALAT1, and NEAT1, regulate inflammatory pathways through various molecular mechanisms. For example, they act as competing endogenous RNAs that absorb microRNAs. These regulatory networks influence key signaling cascades involved in neuroinflammation, including Toll-like receptor (TLR)-mediated pathways, the NF-κB signaling axis, and NLRP3 inflammasome activation. In this review, we summarize and categorize glial lncRNAs according to their molecular interactions and functional roles in disorders related to cognitive decline. By integrating current evidence, we highlight the contribution of lncRNA-mediated regulatory networks to neuroinflammatory processes and discuss their potential as biomarkers and therapeutic targets. Our findings suggest that glial lncRNAs are crucial regulators of neuroinflammation in cognitive disorders. Their ability to modulate pathways such as the NLRP3 inflammasome makes them promising diagnostic biomarkers and therapeutic targets. Targeting these molecular networks provides new opportunities to halt neurodegeneration and improve clinical outcomes.
Chiara Malatino, Ivana Raffaele, Angelo Quartarone et al.· Frontiers in Aging Neuroscie...· 0 citations
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