Candidate Review:

A Novel Pathophysiological Gene-Environment Interaction Suppresses the Neurotoxic Activities of (Mn) and Mutant HD

Gunnar F. Kwakye* and Aaron B. Bowman§

*Neuroscience Graduate Program, Vanderbilt University Medical School, U1205 Medical Center North, Nashville, TN 37232, USA.
§Department of Neurology, Vanderbilt University, Nashville, TN 37232, USA.
Correspondence to G.K. e-mail: gunnar.f.kwakye@vanderbilt.edu

Abstract | Full Text | PDF

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration, emotional disturbance, and psychiatric disorder, which were first described by George Huntington in1872. Prevalence of HD is approximately 5 in 100,000 worldwide and 1 in 10,000 in the United States with a median age of onset at 391. Surprisingly, approximately 5% of patients have a juvenile form of the disease characterized by increased repeat length in comparison with adult HD onset. Unfortunately, there is currently no effective treatment for the disease. HD is caused by an expansion of a glutamine-encoding triplet repeat (CAG) in the huntingtin gene (IT15)1,2,3. Interestingly, both genetic and environmental factors have been reported to contribute to variability in age of disease onset. In fact, monozygotic twin4,5,6,7 and Venezuelan kindred studies8 have revealed significant environmental influences on the age of onset and clinical presentation of HD. The neuropathology of HD is characterized by selective degeneration of medium spiny neurons (MSNs) in the corpus striatum. The clinical presentation of HD reflects this selective vulnerability with patients exhibiting choreatic hyperkinetic movements. However, as the disease progresses, subsets of neurons within the cortex are lost, whereas the brainstem, cerebellum and hippocampus remain unaffected1. Several potential cellular mechanisms of HD neurotoxicity are supported by experimental evidence including alterations in iron homeostasis, energy metabolism, transcriptional regulation, brain-derived neurotophic factor (BDNF) signaling, axonal transport and altered calcium signaling9-14. A significant challenge in HD neuropathology is segregating the cellular pathologies into direct and indirect effects of HD neurotoxicity. This review will provide insights into studies that examine how metal ions modulate HD neuropathology. A discussion on wild-type huntingtin protein function and its relation to HD will commence the review, followed by environmental factors and aggregates in HD. The review will conclude with metal ion (manganese) essentiality and how its transport mechanisms may play a role in HD pathology.