Polyglutamine (polyQ) disorders are monogenic neurodegenerative disorders. Currently, no therapies are available for this complex group of disorders. Here, we aim to provide an overview of recent promising preclinical studies and the ongoing clinical trials focusing on molecular therapies for polyQ disorders.
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| http://dx.doi.org/10.1016/j.molmed.2024.05.004 | DOI Listing |
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Ubiquitin specific peptidase 11 knockdown slows Huntington's disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway.
Mol Med
January 2025
Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China.
Background: Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington's disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein degradation. However, its specific role in HD is unclear.
View Article and Find Full Text PDFErinacine A-Enriched Mycelium Ethanol Extract Lessens Cellular Damage in Cell and Models of Spinocerebellar Ataxia Type 3 by Improvement of Nrf2 Activation.
Antioxidants (Basel)
December 2024
Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan.
Spinocerebellar ataxia type 3 (SCA3), caused by the abnormal expansion of polyglutamine (polyQ) in the ataxin-3 protein, is one of the inherited polyQ neurodegenerative diseases that share similar genetic and molecular features. Mutant polyQ-expanded ataxin-3 protein is prone to aggregation in affected neurons and is predominantly degraded by autophagy, which is beneficial for neurodegenerative disease treatment. Not only does mutant polyQ-expanded ataxin-3 increase susceptibility to oxidative cytotoxicity, but it also hampers antioxidant potency in neuronal cells.
View Article and Find Full Text PDFL-arginine in patients with spinocerebellar ataxia type 6: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
EClinicalMedicine
December 2024
Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
Background: Therapeutic advancements for the polyglutamine diseases, particularly spinocerebellar degeneration, are eagerly awaited. We evaluated the safety, tolerability, and therapeutic effects of L-arginine, which inhibits the conformational change and aggregation of polyglutamine proteins, in patients with spinocerebellar ataxia type 6 (SCA6).
Methods: A multicenter, randomized, double-blind, placebo-controlled phase 2 trial (clinical trial ID: AJA030-002, registration number: jRCT2031200135) was performed on 40 genetically confirmed SCA6 patients enrolled between September 1, 2020, and September 30, 2021.
Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways.
bioRxiv
December 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 5 South, Baltimore, MD21287.
Huntington's Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD.
View Article and Find Full Text PDFA nucleolar mechanism suppresses organismal proteostasis by modulating TGFβ/ERK signalling.
Nat Cell Biol
January 2025
Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, the Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, ageing-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late-onset neurodegenerative disorders, such as Alzheimer's disease. Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases.
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