Targeting Expanded Repeats by Small Molecules in Repeat Expansion Disorders

Nakamori, Mikihito; Mochizuki, Hideki

doi:10.1002/mds.28397

Cited by 9 publications

(6 citation statements)

References 69 publications

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“…Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability in repeat expansion disorders, such as DM1. 52 To examine whether the expression of these genes involved in DNA repair relates to the differences in repeat instability in each CNS cell lineage of DM1, we analyzed gene expression of mismatch repair genes ( MSH2 , MSH3 and MSH6 ) and FAN1 . There was no difference between the DM1 and control groups in each CNS cell lineage, but there was a trend toward a lower expression of these genes in the spinal cord than in the cortex and white matter ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Nakamori

Shimizu

Ogawa

et al. 2022

Brain Communications

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Myotonic dystrophy type 1 is a multisystem genetic disorder involving the muscle, heart and CNS. It is caused by toxic RNA transcription from expanded CTG repeats in the 3′-untranslated region of DMPK, leading to dysregulated splicing of various genes and multisystemic symptoms. Although aberrant splicing of several genes has been identified as the cause of some muscular symptoms, the pathogenesis of CNS symptoms prevalent in patients with myotonic dystrophy type 1 remains unelucidated, possibly due to a limitation in studying a diverse mixture of different cell types, including neuronal cells and glial cells. Previous studies revealed neuronal loss in the cortex, myelin loss in the white matter and the presence of axonal neuropathy in patients with myotonic dystrophy type 1. To elucidate the CNS pathogenesis, we investigated cell type-specific abnormalities in cortical neurons, white matter glial cells and spinal motor neurons via laser-capture microdissection. We observed that the CTG repeat instability and cytosine–phosphate–guanine (CpG) methylation status varied among the CNS cell lineages; cortical neurons had more unstable and longer repeats with higher CpG methylation than white matter glial cells, and spinal motor neurons had more stable repeats with lower methylation status. We also identified splicing abnormalities in each CNS cell lineage, such as DLGAP1 in white matter glial cells and CAMKK2 in spinal motor neurons. Furthermore, we demonstrated that aberrant splicing of CAMKK2 is associated with abnormal neurite morphology in myotonic dystrophy type 1 motor neurons. Our laser-capture microdissection-based study revealed cell type-dependent genetic, epigenetic and splicing abnormalities in myotonic dystrophy type 1 CNS, indicating the significant potential of cell type-specific analysis in elucidating the CNS pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Nakamori

Shimizu

Ogawa

et al. 2022

Brain Communications

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“…Although a promising avenue, the issue of off-target effects of the ASOs and other Htt-knockdown approaches in humans is a concern. A recent report described the identification of a chemical that binds expanded CAG tracts and promotes contraction of the repeats, which could have value in the treatment of HD and other CAG-repeat expansion disorders [ 110 , 111 ].…”

Section: The Diseasesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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“…Inefficient repair of tandem repeats often leads to repeat expansions or contractions. There are over one million tandem repeats in the human genome, many of which are polymorphic, and their expansion is causal for many disorders [ 16 , 209 , 210 ] such as Huntington disease, spinocerebellar ataxias, Friedreich ataxia and Fragile X syndrome [ 16 , 209 , 210 ]. There is growing evidence that persistent R-loop formation can result in genomic instability [ 211 ] and R-loops are implicated in a number of diseases including cancers, autoimmune and neurological disorders [ 15 , 43 , 212 ].…”

Section: Non-canonical Secondary Structures In Diseasementioning

confidence: 99%

High-throughput techniques enable advances in the roles of DNA and RNA secondary structures in transcriptional and post-transcriptional gene regulation

Georgakopoulos-Soares

Chan

Ahituv

et al. 2022

Genome Biol

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The most stable structure of DNA is the canonical right-handed double helix termed B DNA. However, certain environments and sequence motifs favor alternative conformations, termed non-canonical secondary structures. The roles of DNA and RNA secondary structures in transcriptional regulation remain incompletely understood. However, advances in high-throughput assays have enabled genome wide characterization of some secondary structures. Here, we describe their regulatory functions in promoters and 3’UTRs, providing insights into key mechanisms through which they regulate gene expression. We discuss their implication in human disease, and how advances in molecular technologies and emerging high-throughput experimental methods could provide additional insights.

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Targeting Expanded Repeats by Small Molecules in Repeat Expansion Disorders

Cited by 9 publications

References 69 publications

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

High-throughput techniques enable advances in the roles of DNA and RNA secondary structures in transcriptional and post-transcriptional gene regulation

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