Contribution of HUWE1 to sex differences in aging and Alzheimer's disease
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Project Summary Until recently, the contribution of chromosomal sex to sex-associated differences in aging and Alzheimer's disease (AD) has been largely ignored. As females possess two X chromosomes, many genes that partially escape X inactivation could be expressed at higher levels in females. Escape from X chromosome inactivation occurs with aging and the degree of inactivation escape varies between genes and cell types. The HECT, UBA and WWE domain containing protein 1 (HUWE1) is an E3 ubiquitin ligase that ubiquitinates over 40 substrates. HUWE1 ubiquitinates and induces the degradation of DNA damage response proteins, transcription factors, and other proteins. The Huwe1 gene is located on the X chromosome and associated with X chromosome-linked intellectual disability. Increased dosages of HUWE1 due to duplication events result in intellectual disability in children with females being normal or less symptomatic than males, likely due to X chromosome inactivation. Mutations in Huwe1 lead to intellectual disability as well, and females can also be severely affected as males. Whether HUWE1 plays a role in aging and AD is not studied. In our data, we discovered that HUWE1 levels are higher in aged female mouse brains compared to young brains. Thus, the primary objective of the proposed studies is to investigate whether Huwe1 escapes inactivation in the brain of female Tg2576 and Tau p301 s mice (and their non-Tg controls), and female humans with and without AD and to determine HUWE1's interactome in the brain of young and aged, male and female Tg2576 and Tau p301s mice (their non-Tg controls). Since clinical research has demonstrated variable efficacy of therapeutic agents in male and female patients, identification of sex-specific mechanisms has significant translational relevance.
