C9orf72 poly-PR helps p53 escape from the ubiquitin-proteasome system and promotes its stability

Review Chemistry, Multidisciplinary

P53: Stability from the Ubiquitin-Proteasome System and Specific 26S Proteasome Inhibitors

Andressa Barban do Patrocinio et al.

Summary: This review discusses the mechanism of protein p53 degradation through the ubiquitin-proteasome system, and how compounds inhibiting the 26S proteasome can treat cancer and other diseases by regulating the stability of p53.

ACS OMEGA (2022)

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Article Cell Biology

Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

Junli Gao et al.

Summary: The study reveals that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and patient-derived neurons. PAR induces R-DPR condensation, promotes stress granule formation and TDP-43 aggregation, and may serve as a potential target for treating c9ALS/FTD.

SCIENCE TRANSLATIONAL MEDICINE (2022)

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Article Cell Biology

A high-throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway

Sonia R. Singh et al.

Summary: The study revealed that ZNF418 activates the ALP, inhibits the UPS, and regulates genes associated with cardiomyocyte structure and function. RNA-seq analysis showed that ZNF418 also plays a role in regulating genes involved in cardiac development and/or hypertrophy.

AUTOPHAGY (2021)

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Article Biochemistry & Molecular Biology

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Maya Maor-Nof et al.

Summary: The repeat expansion in the C9orf72 gene leads to activation of a specific transcriptional program, causing neurodegeneration. Removing p53 in experiments successfully rescued neuronal degeneration and extended survival.

CELL (2021)

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Article Biochemistry & Molecular Biology

p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR

Sinem Usluer et al.

Summary: This study investigated the molecular mechanisms of p53's involvement in poly-PR/GR-mediated neurodegeneration, revealing that p53 physically interacts with poly-PR/GR and triggers liquid-liquid phase separation. It was found that reducing p53 protein levels can protect against the neurotoxic effects of poly-PR/GR. These findings contribute to a better understanding of the role of p53 in poly-PR/GR-associated neurodegeneration.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Review Cell Biology

C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels

Jimmy Beckers et al.

Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two distinct classes of neurodegenerative disorders, sharing genetic, cellular, and molecular features. Common features include hexanucleotide repeat expansions in the C9orf72 gene and accumulation of toxic protein aggregates in affected individuals' nervous systems, potentially caused by toxic gain of function from transcribed HRE RNA or DPRs. Furthermore, alterations in protein homeostasis are suggested as a root cause of disease pathogenesis.

AUTOPHAGY (2021)

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Editorial Material Genetics & Heredity

Open Access: A Role for p53 in c9ALS/FTD?

Charlotte M. Fare et al.

Summary: The study establishes that Poly(PR) remodels the neuronal epigenome to promote proapoptotic p53 activity involving PUMA, which drives neurodegeneration in multiple models.

TRENDS IN GENETICS (2021)

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Article Neurosciences

UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model

Kejing Zhang et al.

Summary: UBQLN2 plays a critical role in reducing poly-GA aggregates and alleviating poly-GA-induced neurotoxicity in C9-ALS/FTD by recognizing HSP70 ubiquitination and promoting poly-GA degradation. Disruption of the interaction between UBQLN2 and HSP70 inhibits poly-GA aggregation in C9ALS/FTD iPSC-derived neurons. Enhancing HSP70 with the chemical compound 17AAG at the adult stage mitigates behavioral defects in poly-GA animals.

NEURON (2021)

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Article Biochemistry & Molecular Biology

Expression of C9orf72 hexanucleotide repeat expansion leads to formation of RNA foci and dipeptide repeat proteins but does not influence autophagy or proteasomal function in neuronal cells

Stina Leskela et al.

Summary: The study found that C9orf72 hexanucleotide repeat expansion leads to the production of RNA foci and DPR proteins, but does not affect autophagy or proteasomal activity. Evidence of proteasomal regulation was observed in N2a cells, while there may be cell type-specific morphology and regulation of DPR proteins in cortical neurons. Further research in other model systems is needed to better understand the impact of C9orf72 HRE on cellular protein degradation pathways and DPR protein levels.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2021)

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Article Neurosciences