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L. B. MENALLED, S. MILLER, J. FITZPATRICK, A. KUDWA, C. MORIN, M. PATRY, M. TERRY, K. HOMA, B. FERETIC, T. HANANIA, A. PARACHIKOVA, R. MUSHLIN, K. LEHTIMAKI, J. PUOLIVÄLI, S. RAMBOZ, D. HOWLAND, S. KWAK

Although the genetic basis of Huntington’s disease (HD) is now well understood, a key question in understanding the mechanisms underlying the disorder is whether the disease results from a toxic gain-of-function in the mutant protein, and/or the loss of some key functions performed by the wild type protein. The huntingtin (htt) protein has been found to play an essential role during embryogenesis, since knockout Hdh mice do not survive gestation (Duyao et al., 1995; Nasir et al., 1995; Zeitlin et al., 1995). Reduction of htt to 50% endogenous levels produces viable mice with no overt phenotypes (Duyao et al., 1995; Zeitlin et al., 1995) however more detailed evaluation has revealed deficits in cognition and motor behavior (Nasir et al., 1995) raising the possibility that lowered htt starting in development may have adverse effects in the mouse. Furthermore, postnatal inactivation of htt in brain and testis produces a progressive behavioral phenotype, neurodegeneration, and reduced survival suggesting that htt is required for neuronal function and survival (Dragatsis et al., 2000).

Reduction of endogenous striatal htt using siRNA in rats expressing Htt171-82Q had no further detrimental effect on neuronal survival nor htt inclusion load indicating that partial inactivation of endogenous WT htt in the adult striatum (~50%) had no major impact on the course of HD pathology (Drouet et al, 2009). More research is needed to further explore the role of WT htt in the adult as well as to determine what level of adult WT htt knockdown will be permissible while attempting to reduce the mutant Htt protein.

We present here the first comprehensive behavioral analysis of the effects of a conditional knock-down (starting at 4.5 weeks of age) of WT endogenous htt in adult mice in the absence of any potential mutant gain-of-function. The behavioral battery assessed the motor, general health, cognitive, emotional domains as well as the sensory motor capabilities. Knocking down the endogenous htt protein resulted in significant decrease in body weight and hyperactive behavior in the open field. In addition, significant cognitive, emotional and sensory gating abnormalities were detected in the knock-down mice. Knock-down mice presented an longer latency to fall from the rotarod. Retinal degeneration and/or cataracts were observed in the huntingtin knock-down mice doxycycline treated and untreated. MRI volumetric analysis detected significant reduction of volume of whole brain, striatum and hippocampus at 24 weeks of age in the knock-down mice. These data indicate that the disease mechanism may at least be partially driven by a loss-of-function in the htt protein.