Editors' ChoiceNeurodegenerative Disease

Connecting the Dots in Frontotemporal Dementia

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Science Translational Medicine  05 Oct 2011:
Vol. 3, Issue 103, pp. 103ec161
DOI: 10.1126/scitranslmed.3003255

Frontotemporal dementia (FTD) is an incurable neurodegenerative disease striking individuals between the ages of 40 and 65 years and resulting in behavioral changes, motor abnormalities, and speech impairment. FTD accounts for approximately one-fourth of the cases of early-onset dementia and is currently the second most common cause of presenile dementia. Nearly half of FTD patients have a family history of the disease, which suggests a strong genetic component. Mutations in the gene-encoding progranulin (GRN) have been implicated in FTD, but the function of this protein is unknown. Using cultured primary human neural progenitor cells, animal models, and human brain tissue, Rosen et al. now report that GRN mutations resulting in loss of the GRN protein lead to activation of Wnt signaling, which helps to protect neurons from undergoing apoptosis. This study identifies Wnt and its receptor Frizzled2 as potential new therapeutic targets for treating FTD.

Knowing that loss of GRN activity because of mutation precedes death of neurons in FTD, the researchers developed an in vitro model of GRN loss using human neural progenitor cells. To uncover the gene expression changes contributing to neuronal death, the group performed a genome-wide transcriptome and weighted gene coexpression network analysis. They identified a network of interconnected genes that were dysregulated as a result of GRN loss. Their analysis unexpectedly connected activation of the Wnt signaling pathway to loss of the mutant GRN protein. Translating their findings to human disease, they performed the same gene expression analysis on post-mortem brain tissue from FTD patients. Specifically, they observed up-regulation of the Wnt receptor Frizzled2 in the frontal cortex of FTD human brains as well as in the brains of mice engineered to lack GRN. By overexpressing or knocking down expression of the Frizzled2 receptor in vitro, Rosen and colleagues demonstrated that this receptor is important for the promotion of neuronal survival. These results suggest that up-regulation of the Frizzled2 receptor and activation of Wnt signaling in response to loss of GRN may be part of a natural neuroprotective mechanism. Given that agonists of Wnt have been shown to be neuroprotective in other forms of dementia, the new findings suggest that small-molecule Wnt agonists that activate the Frizzled2 receptor may be useful for treating FTD.

E. Y. Rosen et al., Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71, 1030–1042 (2011). [Abstract]

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