PT  - JOURNAL ARTICLE
AU  - Zhang, Yong-Jie
AU  - Xu, Ya-fei
AU  - Dickey, Chad A.
AU  - Buratti, Emanuele
AU  - Baralle, Francisco
AU  - Bailey, Rachel
AU  - Pickering-Brown, Stuart
AU  - Dickson, Dennis
AU  - Petrucelli, Leonard
TI  - Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43
AID  - 10.1523/JNEUROSCI.3421-07.2007
DP  - 2007 Sep 26
TA  - The Journal of Neuroscience
PG  - 10530--10534
VI  - 27
IP  - 39
4099  - http://www.jneurosci.org/content/27/39/10530.short
4100  - http://www.jneurosci.org/content/27/39/10530.full
SO  - J. Neurosci.2007 Sep 26; 27
AB  - TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.