TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms DOI
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 4, 2024

Abstract The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal isoforms that are predominantly cytosolic localization, highly prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 created as a byproduct autoregulation cleared by nonsense mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD can lead toxicity but rapidly degraded post-translationally. Circumventing regulatory mechanisms overexpressing results neurodegeneration vitro vivo via oligomerization impairment flTDP43 splicing activity, addition binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression provide insight into consequences aberrant accumulation disease.

Язык: Английский

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms DOI Creative Commons
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

и другие.

Cell Reports, Год журнала: 2025, Номер 44(1), С. 115113 - 115113

Опубликована: Янв. 1, 2025

Highlights•Short (s)TDP43 isoforms are created as a by-product of TDP43 autoregulation•sTDP43 is strictly regulated by NMD, the proteasome, and autophagy•sTDP43 potent inhibitor splicing activitySummaryThe nuclear RNA-binding protein integrally involved in pathogenesis amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal that predominantly cytosolic localization, prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 autoregulation cleared nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD rapidly degraded post-translationally via proteasome macroautophagy. Circumventing regulatory mechanisms overexpressing results neurodegeneration oligomerization impairment flTDP43 activity, addition RNA-binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression underscore consequences aberrant accumulation disease.Graphical abstract

Язык: Английский

Процитировано

1
An ANXA11 P93S variant dysregulates TDP‐43 and causes corticobasal syndrome DOI Creative Commons
Allison Snyder, Veronica H. Ryan, James Hawrot

и другие.

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(8), С. 5220 - 5235

Опубликована: Июнь 26, 2024

Abstract INTRODUCTION Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity a novel VUS P93S in Annexin A11 (ANXA11) – an amyotrophic lateral sclerosis/frontotemporal dementia‐associated gene corticobasal syndrome kindred. Established ANXA11 mutations cause aggregation, altered lysosomal‐RNA granule co‐trafficking, and transactive response DNA binding protein 43 kDa (TDP‐43) mis‐localization. METHODS described clinical presentation explored phenotypic diversity variants. P93S's effect on function TDP‐43 biology was characterized induced pluripotent stem cell‐derived neurons alongside multiomic neuronal microglial profiling. RESULTS were linked to cases. led decreased lysosome colocalization, neuritic RNA, nuclear cryptic exon expression. Multiomic signatures implicated immune dysregulation interferon signaling pathways. DISCUSSION This study establishes pathogenicity, broadens spectrum mutations, underscores dysfunction pathophysiology, demonstrates potential cellular models determine variant Highlights is pathogenic variant. Corticobasal part spectrum. Hybridization chain reaction fluorescence situ hybridization (HCR FISH) new tool detection exons due TDP‐43‐related loss splicing regulation. Microglial related pathways are important drivers disease. Cellular powerful tools adjudicating variants significance.

Язык: Английский

Процитировано

4
ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia DOI Creative Commons

Yaping Meng,

Wenping Li, Yanxin Zhang

и другие.

European Journal of Neurology, Год журнала: 2025, Номер 32(5)

Опубликована: Май 1, 2025

ABSTRACT Background Semantic variant primary progressive aphasia (svPPA) is typically a sporadic disorder, and few cases have been linked to ANXA11 mutations. Comprehensive analyses of genetic mutations in svPPA are limited. Furthermore, the clinical distinctions between typical right temporal frontotemporal dementia (rtvFTD) poorly understood. Methods A 68‐year‐old patient with carrying heterozygous c.119A>G (p.D40G) mutation underwent comprehensive neuropsychological, neuroimaging, assessments at baseline one‐year follow‐up timepoint. Additionally, systematic reviews were conducted identify reported FTD spectrum associated svPPA. Clinical‐genetic profiles rtvFTD compared based on data from literature. Results Thirty‐two patients identified, including 11 pure phenotypes majority exhibiting FTD‐amyotrophic lateral sclerosis (ALS). Among 167 svPPA‐related cases, MAPT , GRN C9ORF72 most frequently implicated; primarily identified East Asian patients. Comparative analysis revealed overlapping age onset, disease duration, sex distribution, APOE ε4 allele frequencies but differing presentations. Conclusions This study reports case China p.D40G without ALS‐related features. Our findings highlight importance pathogenesis.

Язык: Английский

Процитировано

0
RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights DOI Creative Commons

JL Rummens,

Sandrine Da Cruz

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Июнь 4, 2025

Язык: Английский

Процитировано

0
TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms DOI
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 4, 2024

Abstract The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal isoforms that are predominantly cytosolic localization, highly prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 created as a byproduct autoregulation cleared by nonsense mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD can lead toxicity but rapidly degraded post-translationally. Circumventing regulatory mechanisms overexpressing results neurodegeneration vitro vivo via oligomerization impairment flTDP43 splicing activity, addition binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression provide insight into consequences aberrant accumulation disease.

Язык: Английский

Процитировано

0