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

Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open‐Label Study DOI Creative Commons
Marc Gotkine, David Schoenfeld,

Ilana Cohen

et al.

Muscle & Nerve, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

ABSTRACT Introduction/Aims Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention this devastating progressive disease. This first‐in‐human study evaluated the safety, tolerability, and preliminary efficacy of activator, IPL344, ALS. Methods Nine participants ALS progression rate > 0.55 points/month on Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS‐R) received open‐label IPL344 treatment (once‐daily) up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before after treatment. Clinical outcomes compared historical data. Results The mean ± SD duration follow‐up 14.0 12.5 One participant developed drug hypersensitivity, two had central venous catheter‐related AEs, serious pneumonia AEs. unadjusted SE slope decline ALSFRS‐R −0.53 0.15 (48% slower vs. controls, p = 0.028). Adjustment disease stage rate‐indicating covariates indicated 64% ( 0.034), increased rather than reduced body weight 0.02). Eight nine IPL344‐treated significantly improved median matched control group 0.04). NfL lowered by 27% n 6). Unadjusted survival 43.4 months [95% CI: 20.5, NA] 19.1 [17.4, 23.0] group. Discussion These data indicate that safe well‐tolerated, possibly effective. Our findings may merit further investigation larger placebo‐controlled clinical trial.

Language: Английский

Citations

0
Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs DOI
Dia Advani, Pravir Kumar

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: March 26, 2024

Language: Английский

Citations

4
Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations DOI Creative Commons
Francesco Liguori, Francesca Alberti, Susanna Amadio

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(5), P. 167192 - 167192

Published: April 22, 2024

Several mutations in the SOD1 gene encoding for antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration patients' death within 2–5 years from diagnosis. Motor loss related symptomatology manifest mostly adult life and, to date, there is still gap of knowledge on precise cellular molecular events preceding neurodegeneration. To deepen our awareness early phases disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either mutation A4V or G85R human (hSOD1A4V hSOD1G85R). We demonstrate that pan-neuronal expression hSOD1A4V hSOD1G85R pathogenic construct impairs survival performance transgenic flies. Moreover, protein transcript analysis fly heads indicates mutant hSOD1 induction stimulates glial marker Repo, up-regulates IMD/Toll immune pathways through antimicrobial peptides interferes oxidative metabolism. Finally, cytological larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters found modulated timeframe when neurodegeneration not detected. The novelty work twofold: have expressed first time all neurons confirmed some ALS-related pathological phenotypes flies, confirming power generating ALS-like phenotypes. pathogenesis aberrations up-regulation. These findings were unexplored SOD1-ALS field.

Language: Английский

Citations

4
Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain DOI Creative Commons
Aris Polyzos, Ana Cheong,

Jung Hyun Yoo

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 4, 2024

Language: Английский

Citations

4
Transcript errors generate amyloid-like proteins in huwman cells DOI Creative Commons

Claire S. Chung,

Yi Kou,

Sarah J. Shemtov

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 7, 2024

Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, molecular mechanisms which these arise remain unclear. Here, we demonstrate are produced in a variety human cell types, including stem cells, brain organoids and fully differentiated neurons mistakes occur messenger RNA molecules. Some generate mutant already known to cause disease, while others have not been observed before. Moreover, show increase when cells exposed DNA damage, major hallmark aging. When taken together, experiments suggest mechanistic link between normal aging process age-related diseases.

Language: Английский

Citations

4
Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies DOI Creative Commons

Anna R. Dashtmian,

Fereshteh B. Darvishi,

W. David Arnold

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(11), P. 928 - 928

Published: May 28, 2024

Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses upper lower motor neurons. Treatment ALS limited, survival 2–5 years after disease onset. While can occur younger individuals, the risk significantly increases with advancing age. Notably, both forms share pathophysiological features overlapping hallmarks aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, cellular senescence. This review explores chronological biological context onset progression. Age-related muscle weakness unit loss mirror aspects pathology coincide peak incidence, suggesting potential link between development. Hallmarks aging, DNA senescence, are implicated ALS, offering insights into shared mechanisms underlying pathogenesis. Furthermore, senescence-associated secretory phenotype senolytic treatments emerge as promising avenues for intervention, to mitigate neuroinflammation modify

Language: Английский

Citations

2
Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration DOI Open Access

Megumi Asada‐Utsugi,

Makoto Urushitani

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7906 - 7906

Published: July 19, 2024

Neurons in the brain are continuously exposed to various sources of DNA damage. Although mechanisms damage repair mitotic cells have been extensively characterized, pathways post-mitotic neurons still largely elusive. Moreover, inaccurate can result deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting existence neuron-specific mechanisms. Our research has centered on microtubule-associated protein tau (MAPT), a crucial pathological implicated neurodegenerative diseases, its interplay with neurons' response (DDR). This review aims provide an updated synthesis current understanding complex between DDR cytoskeletal proteins neurons, particular focus role disorders.

Language: Английский

Citations

2
C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress DOI Creative Commons
M.E. Cicardi,

Justin Hallgren,

Darilang Mawrie

et al.

iScience, Journal Year: 2023, Volume and Issue: 26(9), P. 107505 - 107505

Published: July 28, 2023

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is aberrantly translated sense and antisense directions into dipeptide proteins, among which poly proline-arginine (PR) displays most aggressive neurotoxicity in-vitro in-vivo. PR partitions to nucleus when heterologously expressed neurons other cell types. We show that by lessening nuclear accumulation of PR, we can drastically reduce its neurotoxicity. strongly accumulates nucleolus, a structure critical regulating stress response. determined that, neurons, caused nucleolar increased levels transcription factor p53. Downregulating p53 also prevented PR-mediated both in-vivo models. investigated if could induce senescence phenotype neurons. However, did not observe any indications such an effect. Instead, found evidence for induction programmed death via caspase-3 activation.

Language: Английский

Citations

6
Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis DOI Creative Commons
Minggang Fang, Sara K. Evans, Alissa L. Nana

et al.

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Oct. 2, 2023

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization aggregation DNA/RNA-binding protein TDP-43, but how loss nuclear TDP-43 function contributes to ALS FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP , which encodes as a gene whose loss-of-function results in elevated DNA mutation rate genomic instability. Consistent with this finding, observe increased damage induced pluripotent stem cells (iPSCs) iPSC-derived post-mitotic neurons generated from patients harboring mutations. We find that increase due defects two major pathways for double-strand break repair: non-homologous end joining homologous recombination. Cells repair are sensitive damaging agents and, accordingly, show marked reduction survival following treatment agent. Importantly, also observed depletion ALS/FTD patient brain tissues. Collectively, our demonstrate have levels contribute idea instability defining feature pathology.

Language: Английский

Citations

5
C9orf72poly(PR) mediated neurodegeneration is associated with nucleolar stress DOI Creative Commons
M.E. Cicardi,

JH Hallgren,

Darilang Mawrie

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 16, 2023

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is translated into dipeptide proteins, among which poly-proline-arginine (PR) displays most aggressive neurotoxicity in-vitro and in-vivo . PR partitions to nucleus when expressed neurons other cell types. Using drosophila primary rat cortical as model systems, we show that by lessening nuclear accumulation of PR, can drastically reduce its neurotoxicity. accumulates nucleolus, a site ribosome biogenesis regulates stress response. We examined effect nucleolar impact on function determined caused increased levels transcription factor p53. Downregulating p53 levels, either genetically or increasing degradation, also prevented PR-mediated neurotoxic phenotypes both models. investigated whether could cause senescence phenotype but observed none. Instead, found induction apoptosis via caspase-3 activation. In summary, uncovered central role dysfunction upon expression context C9-ALS/FTD.

Language: Английский

Citations

4