A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

Abstract

The R6/2 transgenic mouse model of Huntington’s disease (HD) carries several copies of exon1 of the huntingtin gene that contains a highly pathogenic 120 CAG-repeat expansion. We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6/2 mice at a pre-symptomatic (e.g., embryonic) and symptomatic (e.g., between 3 and 10 weeks postnatal) time points. We identified changes in several signaling cascades, for example, the Akt/FoxO3/CDK2, mTOR/ULK1, and RAF/MEK/CREB pathways. We also identified the Rho-Rac GTPase cascade that contributes to cytoskeleton organization through modulation of the actin-binding proteins, cofilin and profilin. Immunoblotting revealed higher levels of phosphoSer138-profilin in embryonic R6/2 mouse samples (cf. WT mice) that diminish progressively and significantly over the postnatal, symptomatic course of the disease. We detected sex- and genotype-dependent patterns in the phosphorylation of actin-regulators such a ROCK2, PAK, LIMK1, cofilin, and SSH1L, yet none of these aligned consistently with the changing levels of phosphoSer138-profilin. This could be reflecting an imbalance in the sequential influences these regulators are known to exert on actin signaling. The translational potential of these observations was inferred from preliminary observations of changes in LIMK-cofilin signaling and loss of neurite integrity in neural stem cells derived from an HD patient (versus a healthy control). Our observations suggest that a pre-symptomatic, neurodevelopmental onset of change in the phosphorylation of Ser138-profilin, potentially downstream of distinct signaling changes in male and female mice, could be contributing to cytoskeletal phenotypes in the R6/2 mouse model of HD pathology.

Actin Cytoskeleton Polymerization and Focal Adhesion as Important Factors in the Pathomechanism and Potential Targets of Mucopolysaccharidosis Treatment

“…The abnormal morphology of the HD fibroblast is correlated with actin cap deficiency, and it was suggested that this unique feature can be used as a personalized biomarker of HD [ 58 ]. The Rho-Rac GTPase cascade was identified to be involved in the reorganization of the cytoskeleton by actin-binding proteins cofilin and profilin, and it was concluded that the loss of phosphoSer138 in profilin is correlated with the symptomatic course of HD [ 59 ].…”

Infantile spasms‐linked Nedd4‐2 mediates hippocampal plasticity and learning via cofilin signaling

“…These results suggest that Nedd4‐2 may have different substrates and/or different activity toward certain substrates in males versus in females. This could add another layer of complexity about sex‐specific behavior since cofilin signaling is known to be regulated sex‐dependently (Baharani et al , 2020). Reduced exploring activity of female Nedd4‐2 cKO mice in an open field test could suggest altered motor function and/or anxiety behavior, which have both been linked to IS (Price et al , 2009; Asinof et al , 2016; Salar et al , 2018).…”