Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation DOI Creative Commons

Cha Yang,

Cynthia A. Leifer, Jan Lammerding

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(12), P. 107999 - 107999

Published: Nov. 15, 2024

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Thus it crucial to understand molecular mechanism regulating homeostasis. Here, we show that uptake of oligodeoxynucleotides (ODNs) from extracellular space induces reversible puncta formation both neurons glia. ODNs facilitate liquid-liquid phase separation vitro. Importantly, persistent accumulation DNA cytoplasm leads depletion enhanced production short isoform (sTDP-43). In addition, response ODN uptake, import receptor karyopherin subunit β1 (KPNB1) sequestered cytosolic puncta. ALS-linked Q331K mutation decreases dynamics increases levels sTDP-43. Moreover, are induced damage impaired envelope integrity due Lamin A/C deficiency. summary, our data support abnormal may be one key mechanisms leading proteinopathy provides novel insights into ALS caused mutations.

Language: Английский

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration DOI Creative Commons

Rumiana Tenchov,

Janet M. Sasso, Qiongqiong Angela Zhou

et al.

Published: April 10, 2024

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally polyglutamine tract. A total nine polyQ have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal bulbar muscular (SBMA). The this class each considered rare, yet constitute the largest monogenic disorders. While subtype has its own causative gene, certain pathologic molecular attributes implicated in virtually all diseases, protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, mitochondrial dysfunction. Although animal models disease available helping to understand their pathogenesis access disease-modifying therapies, there is neither cure nor prevention for these only symptomatic treatments available. In paper, we analyze data from CAS Content Collection summarize research progress diseases. We examine publication landscape area effort provide insights into current knowledge advances developments. review most discussed concepts assess strategies combat Finally, inspect clinical applications products against development pipelines. objective broad overview evolving regarding outline challenges, evaluate growth opportunities further efforts combating

Language: Английский

Citations

1
Mouse models to explore the biological and organismic role of DNA polymerase beta DOI
Robert W. Sobol

Environmental and Molecular Mutagenesis, Journal Year: 2024, Volume and Issue: 65(S1), P. 57 - 71

Published: April 1, 2024

Abstract Gene knock‐out (KO) mouse models for DNA polymerase beta (Polβ) revealed that loss of Polβ leads to neonatal lethality, highlighting the critical organismic role this polymerase. While biochemical analysis and gene KO cell lines have confirmed its in base excision repair TET‐mediated demethylation, more long‐lived continue be developed further define role. The Polb ‐KO was first Cre‐mediated tissue‐specific models. This technology exploited investigate roles V(D)J recombination (variable‐diversity‐joining rearrangement), complementation, SPO11‐induced double‐strand break repair, germ genome stability, as well neuronal differentiation, susceptibility genotoxin‐induced damage, cancer onset. revolution knock‐in (KI) made possible by CRISPR/cas9‐mediated editing directly C57BL/6 zygotes. has helped identify phenotypes associated with germline or somatic mutants Polβ. Such KI uncover importance key active site residues specific enzyme activities, such Y265C develops lupus symptoms. More recently, we used mutate two codon changes, yielding L301R/V303R mouse. In model, expressed protein cannot bind obligate heterodimer partner, Xrcc1. Although mutant is proteolytically unstable defective recruitment sites homozygous viable fertile, yet small stature. We expect additional targeted under development are poised reveal new biological

Language: Английский

Citations

1
Mouse models to explore the biological and organismic role of DNA polymerase beta DOI Open Access
Robert W. Sobol

Authorea (Authorea), Journal Year: 2024, Volume and Issue: unknown

Published: March 19, 2024

Ποστεδ ον 19 Μαρ 2024 ͺ Τηε ςοπψριγητ ηολδερ ις τηε αυτηορ/φυνδερ

Citations

1
C9orf72expansion creates the unstable folate-sensitive fragile site FRA9A DOI Open Access

Mila Mirceta,

Monika H.M. Schmidt,

Natalie Shum

et al.

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

Published: Oct. 29, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immuno-stimulatory or damaged unknown. Here, we show in pre-symptomatic ALS-FTD patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb as highly-compacted chromatin embedded an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources immunostimulatory DNA. Cells from contained highly-rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate-deficiency. Age-dependent fragility, can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome adding structural variations disease-enriched 9p21 likely elsewhere.

Language: Английский

Citations

1
Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation DOI Creative Commons

Cha Yang,

Cynthia A. Leifer, Jan Lammerding

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(12), P. 107999 - 107999

Published: Nov. 15, 2024

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Thus it crucial to understand molecular mechanism regulating homeostasis. Here, we show that uptake of oligodeoxynucleotides (ODNs) from extracellular space induces reversible puncta formation both neurons glia. ODNs facilitate liquid-liquid phase separation vitro. Importantly, persistent accumulation DNA cytoplasm leads depletion enhanced production short isoform (sTDP-43). In addition, response ODN uptake, import receptor karyopherin subunit β1 (KPNB1) sequestered cytosolic puncta. ALS-linked Q331K mutation decreases dynamics increases levels sTDP-43. Moreover, are induced damage impaired envelope integrity due Lamin A/C deficiency. summary, our data support abnormal may be one key mechanisms leading proteinopathy provides novel insights into ALS caused mutations.

Language: Английский

Citations

1