A peptidylic inhibitor for neutralizing expanded <i>CAG</i> RNA-induced nucleolar stress in polyglutamine diseases

Zhang, Qian; Chen, Zhefan Stephen; An, Yu; Liu, Haizhen; Hou, Yonghui; Li, Wen; Lau, Kwok‐Fai; Koon, Alex Chun; Ngo, Jacky Chi Ki; Chan, Ho Yin Edwin

doi:10.1261/rna.062703.117

Cited by 24 publications

(45 citation statements)

References 62 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies on cell and fly models of the polyQ-expanded diseases have shown that the expanded CAG RNA interacts with the nucleolin, a nucleolar protein implicated in the synthesis and maturation of ribosomes, thus preventing the preribosomal RNA transcription and leading to a nucleolar stress-induced apoptosis in polyQ diseases [232]. Further experiments demonstrated that a new synthetized nucleolinderived beta-structured inhibitor for neurodegenerative diseases fused together with a TAT peptide, a cell-penetrating peptide that facilitate cellular uptake of different cargos, directly interacted with a CAG-expanded RNA, suppressed the nucleolar stress in cells, inhibited the mutant RNA-induced neurodegeneration in polyQ flies, improved the climbing ability and extended a lifespan of these flies, and finally, suppressed the neurotoxicity in SCA2 and SCA3 cell and fly models [233]. Thus, the exclusion of the mutant polyQ protein from the transcription process and suppression of its altered functions might have a potential therapeutic effect in SCA2.…”

Section: Modifiers Of Transcription Translation and Dna Repairmentioning

confidence: 99%

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Egorova

Bezprozvanny

2019

Neurotherapeutics

View full text Add to dashboard Cite

The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.

show abstract

Section: Modifiers Of Transcription Translation and Dna Repairmentioning

confidence: 99%

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Egorova

Bezprozvanny

2019

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…neurodegenerative disorders, such as Huntington's disease and several spinocerebellar ataxias, the interaction between the expanded CAG RNA and the NCL prevents pre-RNA transcription and induces nucleolar stress (Tsoi et al, 2012;Zhang et al, 2018).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Nucleolin reorganization and nucleolar stress in Purkinje cells of mutant PCD mice

Baltanás

Berciano

Tapia

et al. 2019

Neurobiology of Disease

View full text Add to dashboard Cite

The Purkinje cell (PC) degeneration (pcd) mouse harbors a mutation in Agtpbp1 gene that encodes for the cytosolic carboxypeptidase, CCP1. The mutation causes degeneration and death of PCs during the postnatal life, resulting in clinical and pathological manifestation of cerebellar ataxia. Monogenic biallelic damaging variants in the Agtpbp1 gene cause infantile-onset neurodegeneration and cerebellar atrophy, linking loss of functional CCP1 with human neurodegeneration. Although CCP1 plays a key role in the regulation of tubulin stabilization, its loss of function in PCs leads to a severe nuclear phenotype with heterochromatinization and accumulation of DNA damage. Therefore, the pcd mice provides a useful neuronal model to investigate nuclear mechanisms involved in neurodegeneration, particularly the nucleolar stress. In this study, we demonstrated that the Agtpbp1 gene mutation induces a p53-dependent nucleolar stress response in PCs, which is characterized by nucleolar fragmentation, nucleoplasmic and cytoplasmic mislocalization of nucleolin, and dysfunction of both pre-rRNA processing and mRNA translation. RT-qPCR analysis revealed reduction of mature 18S rRNA, with a parallel increase of its intermediate 18S-5'-ETS precursor, that correlates with a reduced expression of Fbl mRNA, which encodes an essential factor for rRNA processing. Moreover, nucleolar alterations were accompanied by a reduction of PTEN mRNA and protein levels, which appears to be related to the chromosome instability and accumulation of DNA damage in degenerating PCs. Our results highlight the essential contribution of nucleolar stress to PC degeneration and also underscore the nucleoplasmic mislocalization of nucleolin as a potential indicator of neurodegenerative processes.

show abstract

“…Details of the assay were previously described (21,60). Cyto-Tox 96 nonradioactive cytotoxicity assay kit (Promega, Madison, WI) was used to study cell viability.…”

Section: Lactate Dehydrogenase Cytotoxicity Assaymentioning

confidence: 99%

AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

Hong

Koon

Chen

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Joseph M. Jez Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein-induced cell death. Using a recombinant and purified polyQ protein (thioredoxin-Huntingtin-Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.

show abstract

A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases

Cited by 24 publications

References 62 publications

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Nucleolin reorganization and nucleolar stress in Purkinje cells of mutant PCD mice

AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

Contact Info

Product

Resources

About