Shankaran, S.S., Capell, A., Hruscha, A.T., Fellerer, K., Neumann, M., Schmid, B., and Haass, C. (2008) FTLD-U linked missense mutations in the progranulin gene reduce progranulin production and secretion. The Journal of biological chemistry. 283(3):1744-1753.
Loss of function mutations in progranulin cause tau-negative frontotemporal lobar degeneration with ubiquitin positive inclusions. A major protein component of these inclusions is TDP-43, which becomes hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments, which apparently translocate from nuclei to the cytoplasm. Most progranulin mutations are nonsense mutations resulting in nonsense-mediated mRNA decay and consequently reduced progranulin protein levels. However, some missense mutations are described, which occur within the signal sequence and mature progranulin. We now demonstrate that a progranulin mutation located within the signal sequence (PGRN A9D) results in cytoplasmic missorting with extremely low expression. In contrast, two other progranulin mutations (PGRN P248L and R432C) are expressed as immature proteins, but are inefficiently transported through and partially degraded within the secretory pathway resulting in a significantly reduced secretion. Thus apparently all progranulin mutations cause reduced protein expression or secretion, although by different cellular mechanisms. To investigate a putative relationship between reduced expression of progranulin and TDP-43 relocalization and deposition, we downregulated progranulin in human cell lines and in zebrafish. Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease characterizing C-terminal fragments could be observed.