Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder

Matthes, Frank; Massari, Serena; Bochicchio, Anna; Schorpp, Kenji; Schilling, Judith; Weber, Stephanie; Offermann, Nina; Desantis, Jenny; Wanker, Erich E.; Carloni, Paolo; Hadian, Kamyar; Tabarrini, Oriana; Rossetti, Giulia; Krauß, Sybille

doi:10.1021/acschemneuro.8b00027

Cited by 26 publications

(21 citation statements)

References 48 publications

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“…There are three well-known neurodegenerative diseases worldwide, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases ( Armstrong and Barker, 2001 ). One of the major causes of those three neurodegenerative diseases is regarded as the abnormal protein aggregation in neurons, including β-amyloid for the pathogenesis and progression of Alzheimer’s disease, α-synulein to form proteinaceous cytoplasmic Lewy bodies for Parkinson’s disease and the aggregate-prone huntingtin protein for Huntington’s disease ( Chen and Tully, 2018 ; Clark et al, 2018 ; Kreutzer and Nowick, 2018 ; Matthes et al, 2018 ; Zhan et al, 2018 ; Zhang et al, 2018 ). Besides, the activation of the NLRP3 inflammasome also serves as a vital factor for the onset and development of neurodegenerative diseases ( Ahmed et al, 2017 ; Fu et al, 2017 ; Li et al, 2017 ; Sarkar et al, 2017 ; Wu et al, 2017 ; Aminzadeh et al, 2018 ; Bai et al, 2018 ; Gong et al, 2018 ; Qi et al, 2018 ).…”

Section: Nlrp3 Inflammasome In Cns Disordersmentioning

confidence: 99%

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

Shao

Cao

2018

Front. Mol. Neurosci.

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Central nervous system (CNS) is one of the largest killers of people’s health all over the world. The overactivation of the immune and inflammatory responses is considered as an important factor, contributing to the pathogenesis and progression of CNS disorders. Among all kinds of immune and inflammatory reaction, the inflammasome, a complex of proteins, has been drawn increasingly attention to by researchers. The initiation and activation of the inflammasome is involved in the onset of various kinds of diseases. The NLRP3 inflammasome, the most studied member of the inflammasome, is closely associated with many kinds of CNS disorders. Here in this review, the roles of the NLRP3 inflammasome in the pathogenesis and progression of several well-known CNS diseases would be discussed, including cerebrovascular diseases, neurodegenerative diseases, multiple sclerosis, depression as well as other CNS disorders. In addition, several therapeutic strategies targeting on the NLRP3 inflammasome for the treatment of CNS disorders would be described in this review.

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Section: Nlrp3 Inflammasome In Cns Disordersmentioning

confidence: 99%

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

Shao

Cao

2018

Front. Mol. Neurosci.

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“…Thus, due to the high risk of off-target effects, furamidine is not a good candidate as an anti-HD drug. Nevertheless, this study shows that small molecules that mask RNA-protein interactions may be active against the mutant HTT protein [29].…”

Section: Rna-targeting Strategiesmentioning

confidence: 75%

“…The link between these molecules induces aberrant HTT protein translation. Matthes et al [29] identified a set of CAG repeat binders, one of which, furamidine, reduced the binding of huntingtin mRNA to several RNA-binding proteins in vitro [29]. Moreover, furamidine also decreased HTT protein levels in an HD cell line model [29].…”

Section: Rna-targeting Strategiesmentioning

confidence: 99%

“…Matthes et al [29] identified a set of CAG repeat binders, one of which, furamidine, reduced the binding of huntingtin mRNA to several RNA-binding proteins in vitro [29]. Moreover, furamidine also decreased HTT protein levels in an HD cell line model [29]. However, this ligand, which can also bind to AU RNAs, CUG RNAs or even the DNA minor groove (AT), seems to bind the CAGrepeat RNA in an unspecific manner and only when present in high concentrations.…”

Section: Rna-targeting Strategiesmentioning

confidence: 99%

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Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Cardoso¹

2018

obm genet

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Some repeats of three or more nucleotides in tandem, which are present in a gene or in its vicinity, tend to increase in number and for this reason are called dynamic mutations. These triplet repeats are unstable and can expand from one generation to the next. According to the expansion size, an unaffected individual can carry a pre-mutation that will expand through generations leading to the development of triplet repeat expansion diseases. The increase in the number of repeats over time leads to earlier development and increased severity of symptoms in affected individuals in successive generations. Although there is still no treatment for this type of disease, several strategies are under investigation. Here, we describe treatment approaches for triplet repeat expansion diseases that have been developed over recent years, using DNA or RNA molecules as targets. Some of these strategies have the potential for future use in gene therapy for trinucleotide repeat disorders.

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“…Molecular Dynamics (MD) simulations significantly help to investigate RNA–ligand interactions [ 15 , 16 , 17 ], complementing experimental work [ 18 ]. MD can shed light on RNA’s structural adaptation/flexibility and molecular recognition [ 19 , 20 , 21 ] under realistic conditions of an ionic solution [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding

et al. 2021

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Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.

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Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder

Cited by 26 publications

References 48 publications

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding

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