Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Progranulin (GRN) mutations are a known cause of frontotemporal dementia (FTD).
• The precise function of GRN within the central nervous system (CNS) is not well understood.
• Identifying GRN's downstream pathways is crucial for understanding FTD pathogenesis.

Purpose of the Study:

• To elucidate the molecular pathways affected by GRN deficiency in human neurons.
• To investigate the role of the Wnt signaling pathway in GRN-related FTD.
• To explore potential therapeutic targets for GRN deficiency-mediated FTD.

Main Methods:

• Weighted gene coexpression network analysis (WGCNA) on a human neural progenitor model of GRN deficiency.
• Analysis of gene expression data from postmortem FTD brain tissue.
• In vitro studies using neuronal models to assess the impact of Wnt receptor Fzd2 modulation on apoptosis and survival.

Main Results:

• GRN deficiency in human neurons significantly alters pathways including apoptosis and ubiquitination.
• The Wnt signaling pathway plays a major, unexpected role in GRN deficiency.
• Wnt receptor Fzd2 upregulation promotes neuronal survival, while its reduction increases apoptosis in vitro.
• Altered Wnt signaling was confirmed in postmortem FTD brain samples.

Conclusions:

• GRN deficiency impacts neuronal function through alterations in apoptosis, ubiquitination, and notably, Wnt signaling.
• The Wnt signaling pathway exhibits an adaptive response to GRN deficiency, suggesting a compensatory mechanism.
• Modulation of Fzd2 and the Wnt pathway presents a potential therapeutic avenue for FTD.