Affiliations: Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA
Correspondence:
[*]
Correspondence to: Scott O. Zeitlin, PhD, Department of Neuroscience, University of Virginia School of Medicine, 409 Lane Rd., Box 801392, MR4-5022, Charlottesville, VA 22908, USA. Tel.: +1 434 924 5011; Fax: +1 434 982 4380; E-mail: [email protected].
Note: [1] Present address: MCRA, LLC, Washington, DC, USA.
Abstract: Background:The Huntingtin (HTT) N-terminal domains encoded by Huntingtin’s (HTT) exon 1 consist of an N17 domain, the polyglutamine (polyQ) stretch and a proline-rich region (PRR). These domains are conserved in mammals and have been hypothesized to modulate HTT’s functions in the developing and adult CNS, including DNA damage repair and autophagy. Objective:This study longitudinally characterizes the in vivo consequences of deleting the murine Htt N-terminal domains encoded by Htt exon 1. Methods:Knock-in mice with a deletion of Htt exon 1 sequences (HttΔE1) were generated and bred into the C57BL/6J congenic genetic background. Their behavior, DNA damage response, basal autophagy, and glutamatergic synapse numbers were evaluated. Results:Progeny from HttΔE1/+ intercrosses are born at the expected Mendelian frequency but with a distorted male to female ratio in both the HttΔE1/ΔE1 and Htt+/+ offspring. HttΔE1/ΔE1 adults exhibit a modest deficit in accelerating rotarod performance, and an earlier increase in cortical and striatal DNA damage with elevated neuronal pan-nuclear 53bp1 levels compared to Htt+/+ mice. However, a normal response to induced DNA damage, normal levels of basal autophagy markers, and no significant differences in corticocortical, corticostriatal, thalamocortical, or thalamostriatal synapses numbers were observed compared to controls. Conclusion:Our results suggest that deletion of the Htt N-terminus encoded by the Htt exon 1 does not affect Htt’s critical role during embryogenesis, but instead, may have a modest effect on certain motor tasks, basal levels of DNA damage in the brain, and Htt function in the testis.
Keywords: Huntingtin, huntingtin exon 1, DNA damage, autophagy, sex ratio
