Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder

[EN] Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD. RPVM used grants (PI17/00011 and PI20/00114) funded by the Instituto de Salud Carlos III (ISCIII, Madrid, Spain). These grants are cofinanced by the European Development Regional Fund ''A way to achieve Europe'' (ERDF). Funds from the Fundacion Ramon Areces (CIVP19S8119) and from CIBERER (ACCI-2019-22) were also used. CTR holds a grant by the Generalitat Valenciana and the European Social Fund (ACIF/2020/366). CIBERER is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases. RVM received an Ayuda Miguel Gil grant (VII Convocatoria Ayudas a la Investigacion MEUHER, 2019, cofinanced by Colegio Oficial de Farmaceuticos de Sevilla and Fundacion Cajasol). RVM has also received funds from the Asociacion Valenciana de Enfermedad de Huntington (AVAEH). Trujillo-Del Río, C.; Tortajada-Pérez, J.; Gómez-Escribano, A.; Casterá, F.; Peiró, C.; Millán, J.; Herrero, M... (2022). Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder. Mechanisms of Ageing and Development. 204:1-13. https://doi.org/10.1016/j.mad.2022.111670