Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease

• Published in: International journal of molecular sciences 2022-08, Vol.23 (16), p.8936
• Main Authors: Merino, Marián, Sequedo, María Dolores, Sánchez-Sánchez, Ana Virginia, Clares, Mª Paz, García-España, Enrique, Vázquez-Manrique, Rafael P, Mullor, José L
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Autophagy; Biocompatibility; Caenorhabditis elegans; Disease; Disease Models, Animal; Gene expression; Hereditary diseases; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - drug therapy; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Manganese; Mn(II) complexes; Models, Theoretical; Oxidative stress; polyQ toxicity; proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Proteostasis; Quinoline; Quinolines - therapeutic use; Quinones; Superoxide dismutase; Toxicity; Ubiquitin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23168936

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.