RNA dysregulation in neurodegenerative diseases

The EMBO Journal, Год журнала: 2025, Номер 44(3), С. 613 - 638

Опубликована: Янв. 9, 2025

Dysregulation of RNA processing has in recent years emerged as a significant contributor to neurodegeneration. The diverse mechanisms and molecular functions underlying underscore the essential role regulation maintaining neuronal health function. molecules are bound by RNA-binding proteins (RBPs), interactions between RNAs RBPs commonly affected In this review, we highlight progress understanding dysregulated RNA-processing pathways causes RBP dysfunction across various neurodegenerative diseases. We discuss both established emerging RNA-mediated neuropathogenesis rapidly evolving field. Furthermore, explore development potential RNA-targeting therapeutic approaches for treatment

Язык: Английский

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Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper lower neurons. Whereas most ALS cases are caused combination environmental factors genetic susceptibility, in relatively small proportion cases, disorder results from mutations genes that inherited. Defects several different cellular mechanisms processes contribute to selective neurons (MNs) ALS. Prominent among these accumulation aggregates misfolded proteins or peptides which toxic These accumulating stress ability endoplasmic reticulum (ER) function normally, cause defects transport between ER Golgi, impair RNA, proteins, organelles, such as mitochondria, within axons dendrites, all degeneration MNs. Although dysfunction variety combines towards pathogenesis ALS, this review, we focus on recent advances concerning involvement defective stress, vesicular axonal transport. Graphical

Язык: Английский

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Prion-like Spreading of Disease in TDP-43 Proteinopathies

Brain Sciences, Год журнала: 2024, Номер 14(11), С. 1132 - 1132

Опубликована: Ноя. 9, 2024

TDP-43 is a ubiquitous nuclear protein that plays central role in neurodegenerative disorders collectively known as proteinopathies. Under physiological conditions, primarily localized to the nucleus, but its pathological form it aggregates cytoplasm, contributing neuronal death. Given association with numerous diseases, particularly ALS and FTLD, mechanisms underlying aggregation impact on function have been extensively investigated. However, little still about spreading of this pathology from cell cell. Recent research has unveiled possibility may possess prion-like properties. Specifically, misfolded can act templates inducing conformational changes native molecules propagating state across neural networks. This review summarizes mounting most recent evidence vitro vivo studies supporting hypothesis mechanisms. The behavior significant implications for diagnostics therapeutics. Importantly, emerging strategies such small molecule inhibitors, immunotherapies, gene therapies targeting propagation offer promising avenues developing effective treatments. By elucidating spreading, we therefore aim pave way novel TDP-43-related diseases.

Язык: Английский

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β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Март 20, 2024

Introduction The study of the pathophysiology Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation microtubule associated protein tau (MAPT), inflammation and neurodegeneration. Methods humanized APP NL-G-F knock-in mouse line was crossed to PS19 MAPT P301S , over-expression create dual APPNL-G-F/PS19 MAPTP301S line. resulting pathologies were characterized immunochemical methods PCR. Results We now report on a double transgenic /PS19 at 6 months age exhibits robust A plaque accumulation, intense pathology, strong extensive presence pathology potentiated other neither changed levels amyloid precursor nor accumulation. Interestingly, immunofluorescence in cleared brains indicates microglial generally stronger hippocampus, dentate gyrus entorhinal cortex, which are regions with predominant pathology. /MAPT model also showed accumulation N -methyladenosine (m A), recently shown be elevated brain. m primarily accumulated neuronal soma, but co-localized subset astrocytes microglia. corresponded increases METTL3 decreases ALKBH5, enzymes add or remove m6A from mRNA, respectively. Discussion Our understanding recapitulates many features beginning aging, thus represents useful new for field.

Язык: Английский

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TDP43 and Huntingtin Exon-1 Undergo A Conformationally Specific Interaction That Strongly Alters the Fibril Formation of Both Proteins

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(9), С. 107660 - 107660

Опубликована: Авг. 13, 2024

Protein aggregation is a common feature of many neurodegenerative diseases. In Huntington's disease, mutant huntingtin the primary aggregating protein, but other proteins, such as TDP43, likely to further contribute toxicity. Moreover, also risk factor for TDP pathology in ALS. Despite this co-pathology and it remains unknown whether these amyloidogenic proteins directly interact with each other. Using combination biophysical methods, we show that aggregation-prone regions both exon-1 (Httex1) TDP43 low complexity domain (TDP43-LCD), conformationally specific manner. This interaction significantly slows Httex1 aggregation, while accelerates TDP43-LCD aggregation. A key intermediate responsible effects complex formed by liquid condensates fibrils. shields seeding competent surfaces fibrils from monomers, which are excluded condensates. contrast, undergo an accelerated liquid-to-solid transition upon exposure Cellular studies co-aggregation untagged TDP43. causes mislocalization has been linked The protection lieu interesting, mirrors what found disease models, namely can protect toxicity, promote pathology. These results suggest direct protein could, at least part, be pathologies proteins.

Язык: Английский

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The role of N6-methyladenosine modification in neurodegenerative diseases

Ageing and Neurodegenerative Diseases, Год журнала: 2024, Номер 4(3)

Опубликована: Сен. 5, 2024

In recent years, transcriptomics has emerged as a key focus in neuroscience research, transcriptome modifications play significant role influencing various biological processes. N6-methyladenosine (m6A) represents dynamic and reversible form of mRNA modification prevalent eukaryotes. This is involved virtually every critical stage RNA metabolism, including stability, transcription, translation, splicing, nuclear export, decay, thereby playing pivotal normal brain development. Accumulating evidence suggests that m6A plays substantial neurodegenerative diseases, such Alzheimer’s disease (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS), Huntington’s (HD), while abnormal can lead to neurodevelopmental disorders. review summarizes the relationship between diseases elucidates its potential pathogenic mechanisms at molecular level.

Язык: Английский

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Mo’ m1A, mo’ problems

Cell chemical biology, Год журнала: 2024, Номер 31(1), С. 14 - 16

Опубликована: Янв. 1, 2024

Язык: Английский

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Circadian rhythm in neurodegenerative disease: the role of RNA modifications and potential application of RNA-based therapeutics

Ageing and Neurodegenerative Diseases, Год журнала: 2024, Номер 4(3)

Опубликована: Сен. 21, 2024

Neurodegenerative diseases usually present as progressive impairment of the motor or mental functions central peripheral nervous system, which is often linked to genetic and biochemical factors. The main features include synaptic neuronal deficits, abnormal protein homeostasis, DNA RNA defects, inflammation, pathological aggregation. Clinical evidence suggests that circadian rhythms affect different neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s Huntington’s through oxidative stress, neuroinflammation, other mechanisms. Disruptions in rhythms, are alterations modifications, contribute disease progression. This review provides an overview current research progress on outlines their relationship terms aberrant rhythm, highlights role modifications rhythm-regulated diseases, presents potential applications RNA-based drugs for treating diseases.

Язык: Английский

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m6A modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts

EMBO Reports, Год журнала: 2024, Номер 25(11), С. 5026 - 5052

Опубликована: Окт. 11, 2024

Язык: Английский

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Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer’s Disease

Antioxidants, Год журнала: 2024, Номер 13(10), С. 1225 - 1225

Опубликована: Окт. 12, 2024

Patients with Alzheimer's disease and related dementia (ADRD) are faced a formidable challenge of focal amyloid deposits cerebral angiopathy (CAA). The treatment in ADRD by targeting only oxidative stress, inflammation hyperlipidemia has not yielded significant positive clinical outcomes. chronic high-fat diet (HFD), or gut dysbiosis, is one the major contributors part disrupted transport, epigenetic DNMT1 folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active memory during genes turning off gene writer (DNMT1) eraser (TET2/FTO) transsulfuration pathway mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H

Язык: Английский

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