COMMITTEE FOR AID AND EDUCATION IN NEUROCHEMISTRY (CAEN) CATEGORY 1B: REPORT for Research supplies for use in the applicant’s home laboratory-International Society for Neurochemistry ISN CAEN Grants-April 2016 round RESEARCHER:

Huntington’s Disease (HD) is a neurodegenerative genetic disorder with a prevalence of 5-10/100.000 worldwide and the rate of occurrence is highest in descendents from western European people. HD is caused by a CAG repeat expansion in the huntingtin (Htt) gene that codes for polyglutamine in Htt protein. Mutant Htt accumulates over time and is toxic to neurons, particularly to medium spiny neurons in the striatum [1]. At present, management of HD is limited to treatment of the hyperkinetic movement disorder and psychiatric problems but no treatment modifies the course of the disease. Thus, treatments that slow or prevent disease progression in HD are a major need. Astrocytes are glial cells that exert many essential and complex physiological functions and can become reactive in response to diverse pathological conditions in the brain. Mutant Htt expressed only in mouse astrocytes induces HD-like neurologic symptoms [4]. This suggests that astrocyte may contribute to HD pathogenesis and that they can become new targets for disease treatment. Recently, it was reported that conditioned medium (CM) from astrocytes in culture protected striatum neurons in an animal model of HD [5]. Microglia are the tissue-resident macrophages of the brain and they serve immune surveillance, apoptotic clearance, neurogenesis, and synaptic pruning functions [6]. Microglial cells can also be activated by injury and secrete harmful and/or beneficial molecules that influence neuron survival. In a mouse model of HD, microglia become activated and produce higher levels of pro-inflammatory cytokines than macrophages from the same animals [7]. Thus, the inflammatory response may be involved in HD pathogenesis. Indeed, pro-inflammatory cytokines are elevated in the striatum of HD patients [8]. However, astrocytic or microglial contribution to this response in HD is not well characterized. Reactive astrocytes and microglia are considered detrimental for neurons and this can be true in chronic neuroinflammation. But it is also recognized that glial cells are fundamental in tissue repairing processes and neuron survival. Expression of Htt is ubiquitous and is higher in the brain than in other tissues. Glial cells can also be affected by mutant Htt expression and can contribute to disease progression. Thus, increasing glial viability in neurodegeneration may be a new neuroprotective approach to treat HD. Mitochondrial dysfunction is observed in HD patients and systemic administration of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase from mitochondrial complex II, induces HD-like symptoms in animals and humans [9]. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuron development and survival. BDNF has an anti-apoptotic action in neurons and protective effects on several neurodegenerative diseases like HD [10]. Striatal neurons are dependent on BDNF for their survival and reduced striatal BDNF expression has been observed in HD patients and in HD animal models [11]. Therefore, reduced BDNF expression is proposed to underlie selective striatal cell death in HD. The effects of BDNF have been well studied on neurons but very little is known about its role on astrocytes and microglia.