Generation and Characterization of Knock-in Mouse Models Expressing Versions of Huntingtin with Either an N17 or a Combined PolyQ and Proline-Rich Region Deletion

Background: The polyglutamine (polyQ) stretch of the Huntingtin protein (HTT) in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR). The PRR is a binding site for many HTT-interacting proteins, and the N17 domain regulates several normal HTT functions, including HTT’s ability to associate with membranes and organelles. Objective: This study investigates the consequence of deleting mouse Huntingtin’s (Htt’s) N17 domain or a combination of its polyQ stretch and PRR (QP) on normal Htt function in mice. Methods: Knock-in mice expressing versions of Htt lacking either the N17 domain (Htt(ΔN17)) or both the polyQ and PRR domains (Htt(ΔQP)) were generated, and their behavior, autophagy function, and neuropathology were evaluated. Results: Homozygous and hemizygous Htt(ΔQP/ΔQP), Htt(ΔN17/ΔN17), Htt(ΔQP/–), and Htt(ΔN17/–) mice were generated at the expected Mendelian frequency. Htt(ΔQP/ΔQP) mutants exhibit improvements in motor coordination compared to controls (Htt(+/+)). In contrast, Htt(ΔN17/ΔN17) mutants do not exhibit any changes in motor coordination, but they do display variable changes in spatial learning that are dependent on their age at testing. Neither mutant exhibited any changes in basal autophagy in comparison to controls, but thalamostriatal synapses in the dorsal striatum of 24-month-old Htt(ΔN17/ΔN17) mice were decreased compared to controls. Conclusions: These findings support the hypothesis that Htt’s N17 and QP domains are dispensable for its critical functions during early embryonic development, but are likely more important for Htt functions in CNS development or maintenance.