DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Zhang, Nan; Bewick, Brittani; Schultz, Jason; Tiwari, Anjana; Krencik, Robert; Zhang, Aijun; Adachi, Kaho; Xia, Guangbin; Yun, Kyuson; Sarkar, Partha S.; Ashizawa, Tetsuo

doi:10.1007/s13311-021-01075-w

Cited by 11 publications

(5 citation statements)

References 125 publications

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“…The substrate-binding arms can be varied in length and sequence to allow specific binding to virtually any RNA of interest with high selectivity, entailing a substantial therapeutic and biotechnological potential. For instance, DNAzyme-based therapies could be applied to reduce expression levels of disease-related proteins, such as those involved in cancer, viral diseases or neurodegenerative diseases [6][7][8][9][10][11][12][13]. Yet, DNAzymes often underperform in a cellular environment [3,[14][15][16], obstructing many therapeutic and biotechnological applications.…”

Section: Introductionmentioning

confidence: 99%

The architecture of the 10‐23 DNAzyme and its implications for DNA‐mediated catalysis

et al. 2022

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Understanding the molecular features of catalytically active DNA sequences, so‐called DNAzymes, is essential not only for our understanding of the fundamental properties of catalytic nucleic acids in general, but may well be the key to unravelling their full potential via tailored modifications. Our recent findings contributed to the endeavour to assemble a mechanistic picture of DNA‐mediated catalysis by providing high‐resolution structural insights into the 10‐23 DNAzyme (Dz) and exposing a complex interplay between the Dz's unique molecular architecture, conformational plasticity, and dynamic modulation by metal ions as central elements of the DNA catalyst. Here, we discuss key features of our findings and compare them to other studies on similar systems.

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Section: Introductionmentioning

confidence: 99%

The architecture of the 10‐23 DNAzyme and its implications for DNA‐mediated catalysis

et al. 2022

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“…Several studies on preclinical models showed potential therapies for SCA1, e.g., block of ataxin 1 expression in double mutants [ 73 ], use of antisense oligonucleotides [ 80 , 81 ], enzymatic cleavage of CAG repeat RNA [ 82 ], or neurotransplantation [ 83 ]. However, for SCA1, these approaches are rather in the stage of experimental research and relatively invasive, and safety for human patients needs to be assessed.…”

Section: Discussionmentioning

confidence: 99%

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

Sucha,

Benediktova,

Tichanek

et al. 2023

IJMS

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Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.

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“…Several studies on preclinical models showed potential therapies for SCA1, for instance, block of ataxin 1 expression in double mutants [72], use of antisense oligonucleotides [81,82], enzymatic cleavage of CAG repeat RNA [83], or neurotransplantation [84]. However, for SCA1, these approaches are rather in the stage of experimental research, relatively invasive and safety for human patients needs to be assessed.…”

Section: Discussionmentioning

confidence: 99%

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

Sucha,

Benediktova,

Tichanek

et al. 2023

Preprint

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Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were getting either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.

show abstract

DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Cited by 11 publications

References 125 publications

The architecture of the 10‐23 DNAzyme and its implications for DNA‐mediated catalysis

The architecture of the 10‐23 DNAzyme and its implications for DNA‐mediated catalysis

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

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