Neuroscience and Biobehavioral Reviews 52 (2015) 178–192 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal h om epa ge: www.elsevier.com/locate/neubiorev Review Environmental factors as modulators of neurodegeneration: Insights from gene–environment interactions in Huntington’s disease Christina Mo a,b , Anthony J. Hannan a,c,* , Thibault Renoir a a The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia b Department of Neurobiology, The University of Chicago, Chicago, IL, USA c Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia a r t i c l e i n f o Article history: Received 7 December 2014 Received in revised form 13 February 2015 Accepted 3 March 2015 Available online 10 March 2015 Keywords: Environmental modifiers Tandem repeat disorders Polyglutamine disease Neurodegenerative disorder Alzheimer’s disease Parkinson’s disease Lifestyle Cognitive stimulation Environmental enrichment Exercise Physical activity Stress Diet a b s t r a c t Unlike many other neurodegenerative diseases with established gene–environment interactions, Hunt- ington’s disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin pro- tein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identify- ing environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurode- generative disorders, including Alzheimer’s and Parkinson’s disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mech- anisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfac- tory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, how- ever further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity. © 2015 Published by Elsevier Ltd. Contents 1. Huntington’s disease: a tandem repeat disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 2. Beyond genetic determinism: potential for environmental contributions to HD onset and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 2.1. Mouse models of HD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 2.2. Physical and cognitive activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 2.2.1. Cognitive activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 2.2.2. Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 2.3. Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 2.4. Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 2.4.1. Caloric restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 2.4.2. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 2.4.3. Essential fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 2.4.4. Mediterranean diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 2.4.5. Other dietary factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 2.4.6. Conclusions regarding dietary modulation of HD pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 * Corresponding author at: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Kenneth Myer Building, Melbourne, VIC 3010, Australia. Tel.: +61 3 903 56638. E-mail address: anthony.hannan@florey.edu.au (A.J. Hannan). http://dx.doi.org/10.1016/j.neubiorev.2015.03.003 0149-7634/© 2015 Published by Elsevier Ltd.