Huntington’s disease (HD) is an inherited, degenerative disease caused by an expansion of the CAG triplet (cytosine, adenine and guanine) in the first exon of the HTT gene encoding the huntingtin protein. When these expansions are repeated 36 times or more, patients suffer neurodegeneration.
This minority or rare disease, due to its low prevalence, is characterised by a progressive deterioration of motor and cognitive skills and, as a consequence, patients with this pathology manifest chorea (involuntary movements), motor incoordination, psychiatric disorders and cognitive decline.
At present, there is no treatment that slows down or cures the disease. Chorea can hardly be treated with antichoretics and psychiatric problems with standard antidepressants.
However, a recent study carried out by the Molecular, Cellular and Genomic Biomedicine Research group at the La Fe Health Research Institute (IIS La Fe) has revealed the therapeutic potential of activating the enzyme AMP-activated protein kinase (AMPK), using drugs such as metformin, against HD.
After observing an improvement in HD symptoms in animal models, the study is being translated to the clinic by promoting a clinical trial. The trial will investigate the role of metformin as a potential therapy for HD in humans, under double-blind, placebo-controlled conditions.
Metformin is an orally administered anti-diabetic drug used to curb excess glucose in the blood. AMPK is an enzyme complex that is activated by energy dips in the cell, but also by alarm signals produced by different types of stress, including mutant huntingtin. When AMPK is activated, it triggers other signals and sets in motion ‘clearance pathways’ of defective proteins (autophagy and the proteasome system) that should remove mutant huntingtin from the cellular environment.
It is common for huntingtin to block these ‘clearance pathways’ in some HD patients and several animal models. However, activating AMPK, using drugs, has been shown to reactivate these pathways and, in turn, lead to an improvement in the symptoms suffered by animal models of HD.
The article “Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder” published by the group reflects the importance of metformin as a potential treatment for HD and the great utility that AMPK could have as a therapeutic target not only in this neurodegenerative pathology, but also in other more prevalent diseases such as Parkinson’s or Alzheimer’s, which have similar characteristics to HD, such as the aggregation of proteins prone to collapse.
Trujillo-Del Río C, Tortajada-Pérez J, Gómez-Escribano AP, Casterá F, Peiró C, Millán JM, Herrero MJ, Vázquez-Manrique RP. Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder. Mech Ageing Dev. 2022 Jun;204:111670. doi: 10.1016/j.mad.2022.111670. Epub 2022 Mar 30. PMID: 35367225.