Protective Proteolysis in Huntington’s Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy DOI

Yasmeen Alshehabi,

Dale D. O. Martin

Journal of Huntington s Disease, Journal Year: 2024, Volume and Issue: 13(3), P. 267 - 277

Published: July 12, 2024

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by impaired motor function and cognitive decline, ultimately leading to death. HD caused polyglutamine expansion in the N-terminal region of huntingtin (HTT) protein, which linked decreased HTT turnover, increased proteolysis, aggregation, subsequent neuronal In this review, we explore mechanism protective effect blocking proteolysis at D586, has been shown rescue phenotype mouse models. Until recently, remained unclear. Herein, discuss how D586 promotes turnover correcting autophagy, making better autophagy substrate, through post-translational myristoylation G553.

Language: Английский

Exon-Skipping Therapy for Duchenne Muscular Dystrophy: 30 Years Since Its Proposal and the Future of Pseudoexon Skipping DOI Open Access
Masafumi Matsuo

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1303 - 1303

Published: Feb. 3, 2025

Thirty years ago, in 1995, I proposed a fundamental treatment for Duchenne Muscular Dystrophy (DMD) using antisense oligonucleotides (ASOs) to induce exon skipping and restore dystrophin expression. DMD is progressive fatal muscular dystrophy, the establishment of an effective therapy has been pressing demand among patients worldwide. Exon-skipping utilizing ASOs garnered significant attention as one most promising treatments DMD, stimulating global research development efforts ASO technology. Two decades later, 2016, was conditionally approved by U.S. FDA first treatment. This review summarizes current status challenges ASO-based exon-skipping therapies explores prospects pseudoexon ASOs, which holds potential achieving complete cure DMD.

Language: Английский

Citations

0
In vivo CRISPR base editing for treatment of Huntington′s disease DOI

Shraddha Shirguppe,

Michael Gapinske,

Devyani Swami

et al.

Published: July 7, 2024

Huntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal cortical neurons. Importantly, critical event in pathogenesis HD proteolytic cleavage HTT caspase-6, generates fragments N-terminal domain form highly toxic aggregates. Given role proteolysis plays HD, strategies for preventing this process hold potential treating disorder. By screening 141 CRISPR base editor variants targeting splice elements we identified platforms capable producing isoforms resistant to caspase-6-mediated via editing acceptor sequence 13. When delivered striatum rodent model, these editors induced efficient skipping decreased formation fragments, turn reduced aggregation attenuated atrophy. Collectively, results illustrate decrease toxicity HD.

Language: Английский

Citations

1
Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics DOI Creative Commons
Annemieke Aartsma‐Rus, Rob W.J. Collin, Ype Elgersma

et al.

Therapeutic Advances in Rare Disease, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

Antisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability each ASO ranges from thousands patients worldwide single individuals based on prevalence causative pathogenic variant. It was shown that development individualized ASOs feasible within an academic setting, starting with Milasen treatment patient CLN7 Batten’s disease in USA. Inspired by this, Dutch Center RNA Therapeutics (DCRT) established three medical centers Netherlands track record progressive, neurodegenerative, neurodevelopmental, retinal disorders. The goal DCRT is bundle expertise address national ethical, regulatory, financial issues related treatment, ultimately develop eligible diseases affecting central nervous system academic, not-for-profit setting. In this perspective, we describe establishment 2020 achievements so far, specific focus lessons learned: need processes procedures, global collaboration, raise awareness, fact N-of-1 N-of-a-few.

Language: Английский

Citations

1
Protective Proteolysis in Huntington’s Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy DOI

Yasmeen Alshehabi,

Dale D. O. Martin

Journal of Huntington s Disease, Journal Year: 2024, Volume and Issue: 13(3), P. 267 - 277

Published: July 12, 2024

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by impaired motor function and cognitive decline, ultimately leading to death. HD caused polyglutamine expansion in the N-terminal region of huntingtin (HTT) protein, which linked decreased HTT turnover, increased proteolysis, aggregation, subsequent neuronal In this review, we explore mechanism protective effect blocking proteolysis at D586, has been shown rescue phenotype mouse models. Until recently, remained unclear. Herein, discuss how D586 promotes turnover correcting autophagy, making better autophagy substrate, through post-translational myristoylation G553.

Language: Английский

Citations

0