Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102246 - 102246

Published: Feb. 23, 2024

TAR DNA binding protein-43 (TDP-43) is a key component in RNA splicing which plays crucial role the aging process. In neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, can be mutated, mislocalised out of nucleus neurons glial cells form cytoplasmic inclusions. These alterations lead to its dysregulation contribute mis-splicing various types RNA, mRNA, microRNA, circular RNA. changes result generation an altered transcriptome proteome within cells, ultimately changing diversity quantity gene products. this review, we summarise findings novel atypical RNAs resulting from dysfunction their potential biomarkers or targets for therapeutic development.

Language: Английский

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Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 18, 2024

Language: Английский

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ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Nov. 27, 2024

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 kDa (TDP-43) are pathological hallmarks amyotrophic lateral sclerosis (ALS) its pathogenic mechanism is mediated by both loss-of-function gain-of-toxicity TDP-43. However, the role TDP-43 in oligodendrocytes remains unclear. To investigate impact excess on oligodendrocytes, we established transgenic mice overexpressing ALS-linked mutant TDP-43M337V through crossbreeding with Mbp-Cre mice. Two-step floxed resulted heterozygous low-level systemic expression (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression TDP-43M337V. Although Cre-negative also exhibit subtle motor dysfunction, aggravated clasping signs gait disturbance accompanied myelin pallor corpus callosum white matter lumbar spinal cord Cre-positive RNA sequencing analysis oligodendrocyte lineage cells isolated from whole brains 12-month-old revealed downregulation myelinating marker genes cholesterol-related crucial for myelination, along marked upregulation apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3–positive surrounded activated microglia astrocytes aged Collectively, our findings demonstrate that an amount exacerbates dysfunction mice, likely neuroinflammation. Therefore, targeting protection, particularly ameliorating pathology, could represent a potential therapeutic approach ALS.

Language: Английский

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Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

Cells, Journal Year: 2023, Volume and Issue: 12(22), P. 2660 - 2660

Published: Nov. 20, 2023

While it is well known that 98–99% of the human genome does not encode proteins, but are nevertheless transcriptionally active and give rise to a broad spectrum noncoding RNAs [ncRNAs] with complex regulatory structural functions, specific functions have so far been assigned only tiny fraction all transcripts. On other hand, striking observation an overwhelmingly growing ncRNAs, in contrast modest increase number protein-coding genes, during evolution from simple organisms humans, strongly suggests critical essentially unexplored roles for health disease pathogenesis. Research into vast realm past decades thus lead profoundly enhanced appreciation multi-level complexity genome. Here, we address few many huge remaining knowledge gaps consider some newly emerging questions concepts research. We attempt provide up-to-date assessment recent insights obtained by molecular cell biological methods, application systems biology approaches. Specifically, discuss current data regarding two topics high interest: (1) By which mechanisms could evolutionary ncRNAs types (neural, immune, cardiovascular) constitute novel therapeutic targets diseases? (2) Since causally linked brain evolution, given profound interactions between immune system, human-specific brain-expressed play direct or indirect (immune-mediated) role Synergistic remarkable progress delivery, efficacy, safety nucleic acid-based therapies, ongoing large-scale exploration encouraging proceed development clinical evaluation pathways suggested these research fields.

Language: Английский

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A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 27, 2024

Abstract Background Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development the non-invasive therapeutic access to motor cortex currently limited by presence of blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS +MB ) an emerging technology that was successfully used patients temporarily open cortical BBB. However, FUS -mediated delivery across patients’ BBB has not yet been reported. Similarly, effects on human cells remain unexplored. Methods Here we established first -compatible, fully-human patient-cell-derived model based induced brain endothelial-like (iBECs) study anti-TDP-43 antibody bioeffects vitro . Results Generated iBECs recapitulated disease-specific hallmarks pathology, including changes integrity, permeability TDP-43 proteinopathy. Our results also identified differences between sporadic familial ( C9orf72 expansion carrying) reflecting patient heterogeneity associated disease subgroups. Studies these models revealed successful iBEC monolayer opening lack adverse cellular This accompanied molecular expression tight adherens junction markers, transporter inflammatory mediators, generating transient specific responses. Additionally, demonstrated increase (2.7-fold) (1.9-fold) providing proof-of-concept evidence can be enhance large molecule therapeutics model. Conclusions Together, our describes characterisation responses provides platform for screening

Language: Английский

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