Repetitive elements in aging and neurodegeneration

Trends in Genetics, Год журнала: 2023, Номер 39(5), С. 381 - 400

Опубликована: Март 17, 2023

Язык: Английский

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A-T neurodegeneration and DNA damage-induced transcriptional stress

DNA repair, Год журнала: 2024, Номер 135, С. 103647 - 103647

Опубликована: Фев. 15, 2024

Язык: Английский

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Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Brain, Год журнала: 2023, Номер 146(7), С. 2869 - 2884

Опубликована: Янв. 10, 2023

Abstract Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified hereditary ataxia, heterogeneous group disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants more than 300 genes been described, leading detailed genetic classification partitioned age-of-onset. Despite these advances, up 75% patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as the 100 000 Genomes Project. study aimed understand whether we can improve our knowledge architecture leveraging annotations, and result, generate insights strategies that raise diagnostic yield. To achieve aims, used publicly-available multi-omics data 294 genic features, capturing information relating gene’s structure, variation, tissue-specific, cell-type-specific temporal expression, well protein products gene. We studied features across typically causing childhood-onset, adult-onset or both types disease first individually, then collectively. generation testable hypotheses which investigated using sequencing 2182 individuals presenting 6658 non-neurological probands recruited Using this approach, demonstrated high short tandem repeat (STR) density within childhood-onset suggesting may be missing expansions cohort. was verified childhood- Project who were unexpectedly found trend for higher sizes at naturally-occurring STRs known genes, implying role pathogenesis. unsupervised analysis, significant similarities gene panels, suggested adult- should screened common set. tested assessing burden among vice versa. significantly rare, potentially conventional ataxia. Our analysis has implications current clinical practice testing suggest rate could increased removing age-of-onset partition, through modified screening ataxia-associated effect treating regions candidate loci.

Язык: Английский

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Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome progressive loss coordination from neurodegeneration cerebellum. A commonality across most prevalent is underlying disease mechanism secondary to expansions short tandem DNA repeats. There currently an incomplete understanding pathogenic mechanisms these repeat expansion disorders, core feature which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing study post-mortem brain tissue human donors with range repeat-expansion reveal further mechanistic insights. We compared paired cerebellar frontal cortex data 23 ataxia patients 22 sex-, age-matched controls two banks (spinocerebellar (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreich’s (FRDA), 7 cases unknown molecular diagnoses). analysed for transcript usage, differential cell-type-specific expression transcriptomically profile diseases. also generated cerebellum SCA1, SCA6 FRDA decipher changes in cell type proportions state. Using approach, found that: (i) despite commonalities genetics ataxia, there were components their transcriptional signatures distinct; (ii) extensive evident not only but cases; (iii) activation immune inflammatory pathways, as well involvement non-neuronal types was all lesser or greater extent. This provides novel resource understand ataxia. Furthermore, taken together, results highlight pathways role early potentially important therapeutic targets. These findings provide map transcriptomic pathogenesis.

Язык: Английский

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Forskolin Ameliorates Ataxia Behavior in Purkinje Cell-Celsr3 Cko Mice Via the Camp/Epac Pathway

Опубликована: Янв. 1, 2025

Язык: Английский

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Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(2)

Опубликована: Фев. 1, 2025

Abstract INTRODUCTION Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS We leveraged functional genomics data from Religious Orders Study or Rush Memory and Aging Project (ROS/MAP) Mount Sinai Brain Bank (MSBB) brain biobanks single‐cell RNA‐sequencing HHV‐infected forebrain organoids investigate HHV‐infection‐associated transposable element (TE) dysregulation AD etiologies. RESULTS identified widespread TE in HHV‐positive human brains, including an astrocyte‐specific upregulation of LINE1 subfamily TEs brains. further pinpointed that could potentially regulate target gene NEAT1 expression via long‐range enhancer‐promoter chromatin interactions. This can be partially reversed by usage anti‐HHV drugs (valacyclovir acyclovir) a virus‐infected organoid model. Finally, we demonstrated valacyclovir rescued tau‐associated neuropathology alleviated activation experimental tau aggregation DISCUSSION Our analysis provides associations linking molecular, clinical, neuropathological features with HHV infection, which warrants future clinical validation. Highlights Via bulk RNA‐seq two large‐scale biobanks, ROS/MAP ( n = 109 pathologically confirmed 44 cognitively healthy controls) MSBB 284 150 controls), brains significantly positive RNA abundance APOE4 genotype, Braak staging score, CERAD score. cell type‐specific both microglia astrocytes enhancer–promoter interactions on lncRNA nuclear enriched abundant transcript 1 ). determined acyclovir was associated reduced incidence large real‐world patient database. Using HEK293 P301S model U2OS mt‐Keima model, treatment increased cellular autophagy‐level mechanistically supported benefits data.

Язык: Английский

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Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 22, 2025

Cerebellar ataxia is the primary manifestation of cerebellar degenerative diseases, and mitochondrial dysfunction in Purkinje cells (PCs) plays a critical role disease progression. In this study, we investigated feasibility mitochondria transplantation as potential therapeutic approach to rescue neurodegeneration elucidate associated mechanisms. We constructed conditional Drp1 knockout model PCs (PCKO mice), characterized by progressive ataxia. resulted pervasive apoptosis significant activation surrounding glial cells. Mitochondrial dysfunction, which triggers mitophagy, key pathogenic factor contributing morphological functional damage PCs. Transplanting liver-derived into cerebellum 1-month-old PCKO mice improved function, reduced delayed PCs, alleviated for up 3 weeks. These findings demonstrate that holds promise diseases. ataxia, hallmark degeneration (CBND), driven transplanting CBND improve reduce

Язык: Английский

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Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging

Translational Neurodegeneration, Год журнала: 2025, Номер 14(1)

Опубликована: Март 25, 2025

Abstract Neurological disorders present considerable challenges in diagnosis and treatment due to their complex diverse etiology. Retrotransposons are a type of mobile genetic element that increasingly revealed play role these diseases. This review provides detailed overview recent developments the study retrotransposons neurodevelopment, neuroaging, neurological Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, endogenous retrovirus, important regulatory roles development aging nervous system. They have also been implicated pathological processes several diseases, Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, schizophrenia. provide new perspective for understanding molecular mechanisms underlying diseases insights into diagnostic therapeutic strategies

Язык: Английский

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Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect

Neuron, Год журнала: 2023, Номер 111(5), С. 610 - 611

Опубликована: Март 1, 2023

Язык: Английский

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Navigating the brain and aging: exploring the impact of transposable elements from health to disease

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Фев. 27, 2024

Transposable elements (TEs) are mobile genetic that constitute on average 45% of mammalian genomes. Their presence and activity in genomes represent a major source variability. While this is an important driver genome evolution, TEs can also have deleterious effects their hosts. A growing number studies focused the role brain, both physiological pathological contexts. In believed to be for neuronal plasticity. neurological age-related disorders, aberrant may contribute disease etiology, although remains unclear. After providing comprehensive overview transposable interactions with host, review summarizes current understanding TE within during aging process, context conditions.

Язык: Английский

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