Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease.
Marián MerinoMaría Dolores SequedoAna Virginia Sánchez-SánchezMª Paz ClaresEnrique García-EspañaRafael Pascual Vázquez-ManriqueJosé L MullorPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- oxidative stress
- protein protein
- cell death
- risk factors
- small molecule
- amino acid
- signaling pathway
- hydrogen peroxide
- binding protein
- room temperature
- endoplasmic reticulum stress
- stem cells
- emergency department
- metal organic framework
- mesenchymal stem cells
- resting state
- spinal cord injury
- drug induced
- risk assessment
- functional connectivity