L. B. MENALLED, A. KUDWA, S. MILLER, J. FITZPATRICK, C. MORIN, D. HE, B. ALOSIO, D. FEVERSTON, W. ARIAS, K. HOMA, B. FERETIC, S. DAVIS, R. STEVENSON, J. WATSON-JOHNSON, C. MURPHY, J. PUOLIVALI, J. YRJANHEIKKI, M. HAYDEN, M. POULADI, R. GRAHAM, R. MUSHLIN, E. SCHAEFFER, L. PARK, D. HOWLAND, S. KWAK, S. RAMBOZ
Many functions of huntingtin (htt) protein have been revealed, but the full function is still not completely understood. While Htt null KO mice do not survive to birth (Duyao et al., 1995; Nasir et al., 1995; Zeitlin et al., 1995), mice expressing a 50% reduction of endogenous htt levels reveal cognitive and motor deficits (Nasir et al., 1995) and significant decreases in the number of neurons in globus pallidus and subthalamic nucleus (O’Kusky et al., 1999). Furthermore, postnatal inactivation of htt in brain and testes also produces a progressive behavioral phenotype in mice along with neurodegeneration and reduced survival. In rats expressing Htt171-82Q, however, reduction of endogenous striatal htt using siRNA produced no further reduction in neuronal survival indicating that partial inactivation of endogenous WT htt in the adult striatum (~50%) can be tolerated with no major impact on the course of HD pathology (Drouet et al, 2009). Current therapeutic strategies for HD are targeted at decreasing htt protein levels but more research is needed prior to advancing these therapies. In order to better understand the liabilities associated with reducing normal htt in adult mice, we evaluated the effects of a robust knock down of WT htt both in CNS and periphery in a conditional htt knock-down (KD) model induced by doxycycline. Severe abnormalities were detected including decreased body weight, hyperactivity, abnormal anxiety responses, cognitive deficits, shortened survival and brain atrophy (Menalled et al., SFN 2009). If the abnormal phenotype is due solely to KD of htt, then supplementing KD mice with human htt should rescue these deficits as suggested by prior work showing that human htt rescues embryonic lethality in htt KO mice (Hodgson et al., 1996 and 1999). Therefore, conditional htt knock-down mice were crossed with YAC transgenic mice expressing moderate levels of human WT htt (YAC18 line B60, van Raamsdonk et al., 2006). Offspring were evaluated in a comprehensive behavioral battery under doxycycline treatment. Our data indicates that human htt ameliorates the cognitive deficits observed in the KD mice. These results highlight the potential toxic liabilities of therapies aimed at significantly reducing both WT and MT htt and indicate the need for a better understanding of the lower limits of htt suppression that can be tolerated prior to the onset of toxicity.