Widespread selenium deficiency in the brain of cases with Huntington's disease presents a new potential therapeutic target

Abstract

Background: Huntington or Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterised by both progressive motor and cognitive dysfunction; its pathogenic mechanisms remain poorly understood and no treatment can currently slow, stop, or reverse its progression. There is some evidence of metallomic dysfunction in limited regions of the HD brain; we hypothesised that these alterations are more widespread than the current literature suggests and may contribute to pathogenesis in HD.

Methods: We measured the concentrations of eight essential metals (sodium, potassium, magnesium, calcium, iron, zinc, copper, and manganese) and the metalloid selenium across 11 brain regions in nine genetically confirmed, clinically manifest cases of HD and nine controls using inductively-coupled plasma mass spectrometry. Case-control differences were assessed by non-parametric Mann-Whitney U test (p < 0.05), risk ratios, E-values, and effect sizes.

Findings: We observed striking decreases in selenium levels in 11 out of 11 investigated brain regions in HD, with risk ratios and effect sizes ranging 2.3-9.0 and 0.7-1.9, respectively. Increased sodium/potassium ratios were observed in every region (risk ratio = 2.5-8.0; effect size = 1.2-5.8) except the substantia nigra (risk ratio = 0.25; effect size = 0.1). Multiple regions showed increased calcium and/or zinc levels, and localised decreases in iron, copper, and manganese were present in the globus pallidus, cerebellum, and substantia nigra, respectively.

Interpretation: The observed metallomic alterations in the HD brain may contribute to several pathogenic mechanisms, including mitochondrial dysfunction, oxidative stress, and blood-brain barrier dysfunction. Selenium supplementation may represent a potential, much-needed therapeutic pathway for the treatment of HD that would not require localised delivery in the brain due to the widespread presence of selenium deficiency in regions that show both high and low levels of neurodegeneration.

Funding: In Acknowledgments, includes the Lee Trust, the Endocore Research Trust, Cure Huntington's Disease Initiative, the Oakley Mental Health Research Foundation, the Medical Research Council (MRC), the New Zealand Neurological Foundation, and others.

Keywords: Huntington's disease; Mass spectrometry; Metallomics; Neurodegeneration; Selenium deficiency; Selenium homeostasis.

Fig. 1

Concentrations of Eight Essential Metals and Selenium in HD Cases vs Controls. Data shown are mean ± 95% confidence intervals. Each data point denotes the mean of three biological replicates. Case–control differences determined by Mann–Whitney U test; p < 0.05 was considered significant; n = 7–9. Purple diamonds represent controls and blue circles represent HD cases; error bars denote ±95% CI. C = Controls; CB = cerebellum; CG = Cingulate gyrus; ENT = Entorhinal cortex; GP = Globus pallidus; HD = HD cases; HP = Hippocampus; MCX = Motor cortex; MFG = Middle frontal gyrus; MTG = Middle temporal gyrus; PUT = Putamen; SCX = Sensory cortex; SN = Substantia nigra.

Fig. 2

Each data point denotes the mean of three biological replicates; n = 7–9. Case–control differences determined by Mann–Whitney U test; p < 0.05 was considered significant. Purple diamonds represent controls and blue circles represent HD cases; error bars denote ±95% CI. C = Controls; CB = cerebellum; CG = Cingulate gyrus; ENT = Entorhinal cortex; GP = Globus pallidus; HD = HD cases; HP = Hippocampus; MCX = Motor cortex; MFG = Middle frontal gyrus; MTG = Middle temporal gyrus; PUT = Putamen; SCX = Sensory cortex; SN = Substantia nigra.