Gene–Environment Interactions in Huntington’s Disease

Abstract Huntington's disease (HD) is a neurodegenerative disorder characterized by selective loss of striatal GABAergic medium spiny neurons caused by an excess of CAG repeats in the huntingtin gene ( HTT ). There is an inverse relationship between CAG repeat number and age of onset (AO), but CAG number explains only 60% of the variability in AO, with residual variability caused by environmental factors such as metals, environmental enrichment, exercise, and diet. Exercise and enrichment are beneficial, likely through an associated neuroprotective increase in brain-derived neurotrophic factor. Metals are abnormal in neurons affected by HD, with an excess of copper and iron accumulating in some critical brain regions and a manganese deficit in the striatum, although it is unlikely that metal exposure alone changes HD pathology. However, reduced striatal manganese may limit the function of manganese-dependent neuronal enzymes and their downstream signaling pathways, and this may explain some variability in AO. Understanding the relationship between mutant HTT and neuronal manganese transport dynamics may elucidate additional in vivo functions of the huntingtin protein.