Neurobiology Select

Frontotemporal dementia (FTD) has been linked to mutations in the gene on chromosome 17 that encodes the microtubule-associated protein tau. However, not all patients with FTD have tau mutations even though their disease has been genetically linked to chromosome 17. Such patients exhibit an unusual pathology with ubiquitinimmunoreactive nuclear and cytoplasmic inclusions in layer II of the frontal and temporal neocortex. In companion studies, Baker et al. (2006) and Cruts et al. (2006) set out to determine other genes on chromosome 17 that could be responsible for FTD. Baker et al. (2006) sequenced the DNA of patients from one tau-negative FTD family that showed linkage to chromosome 17 (FTDU-17). Cruts et al. (2006) analyzed the genes within a minimal candidate region from a Dutch family and a Belgian family with FTDU-17. Both groups found mutations (frameshift and nonsense) in the PRGN gene that encodes the growth factor progranulin. Additional analysis of PRGN sequences from a number of other patients confirmed the prevalence in PRGN of frameshift and nonsense mutations that would result in truncated gene products. The authors described several mechanisms through which mutations could interfere with progranulin expression in the brains of FTDU-17 patients. These include nuclear retention and degradation of unspliced PRGN transcripts due to a mutation in a splice donor site, lack of PRGN translation due to a mutation in the translation initiation codon, and nonsense-mediated decay of mutant transcripts. Moreover, expression of truncated mutant progranulin could not be detected in brain tissue extracts or lymphoblasts of patients. Interestingly, both studies found that progranulin does not seem to be part of the neuronal inclusions that are seen in the neocortex of these patients. Taken together, both studies indicate that FTDU-17 is likely due to PRGN loss of function and highlight the importance of progranulin for neuronal survival. Progranulin is important in development, wound repair, inflammation, tumorigenesis, and activation of other growth factors like VEGF. It will be interesting to elucidate the molecular details of how the loss of this growth factor leads to inclusions and neurodegeneration and to determine the protein components of these inclusions. M. Baker et al. (2006). Nature 442, 916–919. Published online July 16, 2006. 10.1038/nature05016. M. Cruts et al. (2006). Nature 442, 920–924. Published online July 16, 2006. 10.1038/nature05017.