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

et al.

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

Published: July 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.

Language: Английский

Fragile X Messenger Ribonucleoprotein Protein and Its Multifunctionality: From Cytosol to Nucleolus and Back DOI Creative Commons
Mohamed S. Taha, Mohammad Reza Ahmadian

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 399 - 399

Published: March 26, 2024

Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack FMR protein (FMRP) synthesis are associated with syndrome, one most common inherited intellectual disabilities. FMRP is multifunctional that involved in many cellular functions almost all subcellular compartments under both normal stress conditions neuronal non-neuronal cell types. This achieved through its trafficking signals, nuclear localization signal (NLS), export (NES), nucleolar (NoLS), as well RNA binding domains, it modulated by various post-translational modifications such phosphorylation, ubiquitination, sumoylation, methylation. review summarizes recent advances understanding interaction networks special focus on stress-related functions, including granule formation, mitochondrion endoplasmic reticulum plasticity, ribosome biogenesis, cycle control, DNA damage response.

Language: Английский

Citations

4
FMRP and its Multifunctionality: From Cytosol to Nucleolus and Back DOI Open Access
Mohamed S. Taha, Mohammad Reza Ahmadian

Published: March 11, 2024

Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack synthesis FMR protein (FMRP) are associated with syndrome, which is one most prevalent inherited intellectual disabilities. FMRP a multifunctional involved in many cellular functions nearly all subcellular compartments under normal conditions stress both neuronal non-neuronal cell types. This achieved through its trafficking signals, nuclear localization signal (NLS), export (NES), nucleolar (NoLS), as well RNA binding domains, modulated by various post-translational modifications such phosphorylation, ubiquitination, sumoylation, methylation. review summarizes recent advances understanding interaction networks special focus on stress-related functions, including granule formation, mitochondrion endoplasmic reticulum plasticity, ribosome biogenesis, cycle control, DNA damage response.

Language: Английский

Citations

1
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

et al.

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

Published: July 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.

Language: Английский

Citations

0