Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease.

Autor:	Wang E; Icahn School of Medicine at Mount Sinai., Pan AL; Icahn School of Medicine at Mount Sinai., Bagchi P; Emory University School of Medicine., Ranjaraju S; Emory University School of Medicine., Seyfried NT; Emory University School of Medicine., Ehrlich ME; Icahn School of Medicine at Mount Sinai., Salton SR; Icahn School of Medicine at Mount Sinai., Zhang B; Icahn School of Medicine at Mount Sinai.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Oct 19. Date of Electronic Publication: 2023 Oct 19.
DOI:	10.21203/rs.3.rs-3453503/v1
Abstrakt:	DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, we utilized stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified patterns of protein expression and phosphorylation that are modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as the activated immune response or suppression of synaptic activities. Upon DUSP4 overexpression, significantly regulated proteins were found in pathways that were suppressed, such as the immune response, in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites that are regulated in 5xFAD compared to WT, and are modulated by DUSP4 overexpression in each sex. Interestingly, the changes in 5xFAD- and DUSP4-associated phosphorylation occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found for the most part in neurons, and play key roles in neuronal processes and synaptic function. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in female, but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice respond to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes, while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex. Competing Interests: Competing interests The authors declare that they have no competing interests. N.T.S. is co-founder of Emtherapro and Arc Proteomics.
Databáze:	MEDLINE
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