I think this is nice, convincing work. However, lots of new questions occur and remain to be answered.

Rosen et al. clearly show (with an overwhelming set of data) for the first time that reduced progranulin (GRN) levels in shRNA-expressing human neuronal progenitor cells, in brains from GRN knockout mice, or in brains of FTLD patients with GRN loss-of-function mutations, result in upregulation of activating components of the Wnt signaling pathway, whereas inhibitors of the Wnt pathway are downregulated. The enhanced Wnt signaling due to GRN deficiency was also observed in mature differentiated cells, and did not depend on cell proliferation. This is of particular interest, since in neurodegenerative diseases, adult differentiated neurons are affected. How GRN expression mechanistically affects the expression of components of the Wnt pathway is not addressed by the authors.

It would be interesting if overexpression of GRN has the opposite effect. In schizophrenia, increased NRG1-, BDNF- and TGF-β signaling and decreased Wnt signaling has been reported (  Read more

I think this is nice, convincing work. However, lots of new questions occur and remain to be answered.

Rosen et al. clearly show (with an overwhelming set of data) for the first time that reduced progranulin (GRN) levels in shRNA-expressing human neuronal progenitor cells, in brains from GRN knockout mice, or in brains of FTLD patients with GRN loss-of-function mutations, result in upregulation of activating components of the Wnt signaling pathway, whereas inhibitors of the Wnt pathway are downregulated. The enhanced Wnt signaling due to GRN deficiency was also observed in mature differentiated cells, and did not depend on cell proliferation. This is of particular interest, since in neurodegenerative diseases, adult differentiated neurons are affected. How GRN expression mechanistically affects the expression of components of the Wnt pathway is not addressed by the authors.

It would be interesting if overexpression of GRN has the opposite effect. In schizophrenia, increased NRG1-, BDNF- and TGF-β signaling and decreased Wnt signaling has been reported (Kalkman, 2009). Since Rosen et al. elegantly show that Wnt signaling is beneficial for neuronal survival upon GRN deficiency, it would be interesting to analyze if growth factor withdrawal in general affects Wnt signaling.

Moreover, Wnt signaling is only increased in GRN mutation carriers, not in FTLD-TDP cases without GRN mutation; therefore, Wnt seems to be no general hallmark of FTLD-TDP, and whether increased Wnt signaling is beneficial for all FTLD-TDP cases remains to be shown. In other neurodegenerative diseases, such as AD and PD, altered Wnt signaling has been reported. Also, Wnt plays a role in maintenance of survival of neurons as a kind of synaptotropic factor. Therefore, I think it is unlikely that the Wnt signaling is specifically involved in FTLD-TDP.

Influencing Wnt signaling pathways might provide therapeutic benefits, though it needs to take into account that Wnt also occurs in oncogenic processes. The Wnt pathway would be a negligible diagnostic tool for GRN mutation carriers because GRN expression in any body fluid is the best diagnostic tool. However, variations in Wnt signaling might contribute to the variable age of disease onset within patients carrying the identical GRN mutation. To investigate whether protective Wnt signaling plays a role for the low disease penetrance for GRN mutation carriers might be quite exciting.

Since we have shown that lysosomal alkalization enhances GRN expression (ARF related news story on Capell et al., 2011), I find it very interesting that the study confirmed that GRN plays an important role in lysosomal function, and that lysosomal genes represent the most significant expression changes in nine-month-old GRN-/- mice.

View all comments by Anja Capell

The study by Dan Geschwind and colleagues using WGCNA is novel and highly interesting, not only providing a general view of transcriptional alterations associated with reduced granulin (GRN) expression, but also uncovering a previously unknown link between GRN and Wnt pathways. Consistent findings of changes in expression of apoptosis and ubiquitination pathway genes in GRN-knocked down neurons and frontotemporal dementia (FTD) brain tissues suggest the clinical relevance of the results. This elegant work represents one of the first systematic studies of neural transcriptome changes in GRN-deficient FTD cases, and will likely stimulate further research in both mechanistic understanding of FTDs and new therapeutic development.

View all comments by Jane Wu