The Metal Mysteries of Huntington’s Disease: A Key to Future Therapies

Huntington disease (HD)  is characterized by an autosomal dominant mutation in the HTT gene, resulting in an expansion of the trinucleotide repeat sequence (CAG) on exon-1 of HTT. This mutation leads to the production of mutated Huntingtin (mHTT), which is a key contributor to the disease’s pathogenesis. This mutated protein gradually damages nerve cells (neurons) in certain areas of the brain, primarily the basal ganglia, which is responsible for coordinating movement. Despite its devastating impact, there are currently no disease-slowing or curative treatments for HD. Therefore, understanding the pathogenic mechanisms and identifying potential therapeutic targets are critical. A recent study led by Dr. Melissa Scholefield, Dr. Stefano Patassini, Dr. Jingshu Xu, and Professor Garth J. S. Cooper, published in the peer-reviewed Journal EBioMedicine. The study investigated metallomic dysfunction in the brains of individuals with HD, shedding light on potential therapeutic targets and mechanisms underlying the disease.

There is no cure for Huntington’s disease, and the condition progressively worsens over time. Treatment is mainly focused on managing the symptoms and improving the quality of life for affected individuals. Medications and therapy can help alleviate some of the emotional and psychiatric symptoms, while physical therapy may assist with mobility and motor skills. Genetic testing can be performed to identify the presence of the mutated HTT gene, which is useful for diagnosing the disease in individuals with a family history. Individuals with a family history of Huntington’s disease may choose to undergo genetic testing for predictive or diagnostic purposes, but this decision should be made carefully, as it has significant emotional and ethical implications. The recent study focused on metallomic dysfunction in the HD brain, with a particular emphasis on essential metals like copper (Cu), manganese (Mn), selenium (Se), and zinc (Zn). These metals play vital roles in antioxidative processes, energy production, and neuronal function. The study’s methodology involved a multi-regional analysis of 11 brain regions in individuals with HD and HD-free controls using inductively coupled plasma mass spectrometry (ICP-MS). This technique allowed for precise quantification of essential metals in brain regions affected to varying degrees by HD.

One of the most striking findings in the study was the consistent decrease in Se levels in all investigated brain regions of HD cases compared to controls. Se is an essential cofactor for antioxidant enzymes and plays a crucial role in protecting against oxidative stress and mitochondrial dysfunction, both of which are implicated in HD pathogenesis. Notably, Se deficiencies have not been previously reported to this extent in the HD brain, making it a promising therapeutic target. Animal studies have suggested that Se supplementation may mitigate oxidative stress and neuronal loss in HD, emphasizing its potential as a therapeutic avenue. However, caution is necessary to avoid Se toxicity, as there is a narrow range of optimal Se levels in the body.

The study also revealed widespread alterations in the sodium (Na) and potassium (K) levels, leading to changes in the Na/K ratio, in several brain regions of HD cases. These alterations may indicate dysfunction in the Na⁺/K+ pump, a crucial element of cellular homeostasis, which plays a significant role in the central nervous system’s electrical signaling. Studies on Na⁺–K⁺ ATPase activity in the HD brain could provide valuable insights into the link between increased glucose levels, oxidative stress, and Na/K dyshomeostasis in HD.

Calcium (Ca) levels were found to be increased in some regions of the HD brain, potentially reflecting hyperexcitotoxicity, a condition where excessive activation of glutamate receptors leads to harmful Ca influx. Such Ca increases could contribute to mitochondrial toxicity, leading to cell damage and neurodegeneration. Investigations into Ca levels and their impact on HD progression may open new avenues for intervention.

The study also identified local alterations in other essential metals like copper (Cu), manganese (Mn), iron (Fe), and zinc (Zn) in the HD brain. These metals are cofactors for a range of essential cellular processes, including antioxidation and neurotransmission. Imbalances in these metals could contribute to oxidative stress, mitochondrial dysfunction, and excitotoxicity in HD.

While the study offers valuable insights into metallomic dysfunction in the HD brain, it has some limitations. The small sample size restricts the ability to detect more subtle metal alterations. Moreover, the lack of data on comorbidities, nutritional status, and other factors in the study participants could introduce confounding variables.

In conclusion, the metallomic disturbances observed in this study suggest that metal imbalances contribute to oxidative stress, mitochondrial dysfunction, and disrupted neuronal function in the HD brain. Selenium deficiency, in particular, stands out as a promising therapeutic target, and further research into safe and effective Se supplementation is warranted. Understanding the roles of other essential metals in HD pathogenesis and their potential as therapeutic targets represents a crucial area of future investigation. While this study offers valuable insights, larger and more diverse cohorts will be needed to confirm these findings and further our understanding of metallomic dysfunction in HD.