Research Highlight:

Bad huntingtin, protective effect

Original Research Article:
BB Williams, D Li, M Wegrzynowicz, BK Vadodaria, JG Anderson, GF Kwakye, M Aschner, KM Erikson, AB Bowman(2010). Disease-toxicant screen reveals a neuroprotective interaction between Huntington’s disease and manganese exposure. J. Neurochem. 112 (1): 227-237.

Huntington’s disease (HD) is a unique neurodegenerative disorder in that it has been mapped to a single locus, the huntingtin gene. In the disease, huntingtin protein progressively undergoes an expansion of a polyglutamate region. Onset of symptoms correlates with a specific number of polyglutamate repeats, such that the disease progressively worsens with age. Thus far, research has been unable to explain how mutant huntingtin leads to a remarkably specific loss of medium spiny neurons in the striatum, a primary cause of the motor deficits seen in patients. One hypothesis is that striatal neurons are situated in an environment that may uniquely impact their vulnerability to mutant HTT; a recent paper from the Bowman lab investigates this gene-environment hypothesis in the context of HD, with specific focus on the impact of metal neurotoxicology.

Williams et al. performed a disease-toxicant interaction screen in order to test a correlation between physiological properties shared between metal exposure and Huntington’s disease. These include oxidative stress, cell stress, protein aggregation, and alterations in calcium signaling and energy metabolism. To test the correlations, they utilized several HD models in metal exposure paradigms. They first demonstrated that a mouse striatal cell line model of HD demonstrates variable cell survival responses to given metals. They note that mutant Huntingtin cells survive at similar rates over a range of concentrations in the vast majority of metals tested. However, mutant cells were less viable when exposed to cadmium and actually displayed a neuroprotective effect in the presence of manganese, without affecting the level of huntingtin protein.

The lab next capitalized on previous research to investigate the impact of manganese on established physiological processes. First, they demonstrated that HD mutant striatal cells have diminished phosphorylation of Akt, a cell stress signaling pathway associated with previous HD studies. They further show that these mutant cells have impaired accumulation of manganese, which may prevent its toxic intracellular effects. Finally they note that in an in vivo mouse model of HD, YAC128Q mice have a striatum-specific reduction of manganese uptake as compared to wild type mice. The neuroprotective effect of mutant HD on manganese exposure is quite surprising, and future experiments will target manganese uptake, export, and storage under the broad hypothesis that HD pathology is regulated in the context of both genetics and environment.