RT Journal Article
SR Electronic
T1 Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 10530
OP 10534
DO 10.1523/JNEUROSCI.3421-07.2007
VO 27
IS 39
A1 Zhang, Yong-Jie
A1 Xu, Ya-fei
A1 Dickey, Chad A.
A1 Buratti, Emanuele
A1 Baralle, Francisco
A1 Bailey, Rachel
A1 Pickering-Brown, Stuart
A1 Dickson, Dennis
A1 Petrucelli, Leonard
YR 2007
UL http://www.jneurosci.org/content/27/39/10530.abstract
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.