Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43.
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 approximately 35 and approximately 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.
Zhang
Yong-Jie
YJ
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
Xu
Ya-fei
YF
Dickey
Chad A
CA
Buratti
Emanuele
E
Baralle
Francisco
F
Bailey
Rachel
R
Pickering-Brown
Stuart
S
Dickson
Dennis
D
Petrucelli
Leonard
L
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006868:Hydrolysis; D002479:Inclusion Bodies / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077153:Progranulins; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin; D053148:Caspase 3; D053179:Caspase 7