ABSTRACT: Investigating Sex-Specific Mechanisms of a Small Molecule Drug in Huntington's Disease for Enhanced Women's Health Huntington's disease (HD) is a devastating neurodegenerative disorder with a complex clinical presentation affecting both males and females. Despite its autosomal dominant inheritance pattern, sex- specific differences in disease manifestation and progression have been observed, likely influenced by hormonal, genetic, and other factors. Presently, a cure for HD remains elusive, and the existing treatments primarily focus on alleviating symptoms and managing disease progression, albeit with limited efficacy. Therefore, new approaches for the treatment of HD are urgently needed. In our pursuit of finding a potential therapeutic candidate for HD, we utilized a novel in-silico fragment scanning approach targeting the surface of mutant huntingtin (mHTT) polyQ. This led us to identify GLYN122 as a promising candidate. In vitro experiments revealed that GLYN122 directly binds to mHTT, reducing its levels and inducing autophagy in neurons. Most exciting, n vivo studies usingGLYN122 demonstrated the ability to cross the blood-brain barrier, reducing mHTT levels in the cortex and striatum of the R6/2 mouse model of HD and subsequently improving motor symptoms. Intriguingly, female R6/2 mice treated with GLYN122 exhibited significant improvements in rotarod performance at 10 weeks of age, whereas male counterparts displayed impaired performance at 8 weeks of age. To advance our understanding of these sex- specific responses to GLYN122 and their underlying mechanisms, we propose to leverage the infrastructure of the Molecular Center of Health and Disease (MCHD)-COBRE. Our research will focus on both male and female HD mouse models, comprehensively assessing behavioral, neuropathological, and molecular aspects. To achieve our objective, we propose to: (1) Investigate sex differences in the therapeutic effects of GLYN122 on motor deficits and neuropathological features in the R6/2 mouse model of HD; and (2) Explore sex differences in mechanistic studies of GLYN122's effects on gene expression and transcriptional regulation in HD. We will assess motor function and neuropathological features using behavioral assessments and histological analyses, respectively. The cores (B-C) of the MCHD-COBRE will uniquely allow us to conduct single cell RNAseq and spatial gene expression analyses, examining how GLYN122 affects gene expression and transcriptional regulation in a cell type specific manner. Our research aims to uncover how GLYN122 affects Huntington's disease (HD) in a sex-specific manner, enhancing its potential as a personalized therapeutic strategy. This aligns with the goals of Administrative Supplements for Research on Women’s Health in the IDeA States (Notice Number: NOT-GM- 22-005), which emphasize studying the influence of sex and gender on complex therapeutic interventions. By exploring sex-specific responses to interventions li...