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The Journal of Neuroscience, September 26, 2007, 27(39):10530-10534; doi:10.1523/JNEUROSCI.3421-07.2007

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Brief Communications
Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43

Yong-Jie Zhang,^1 * Ya-fei Xu,^1 * Chad A. Dickey,² Emanuele Buratti,³ Francisco Baralle,³ Rachel Bailey,¹ Stuart Pickering-Brown,⁴ Dennis Dickson,¹ and Leonard Petrucelli¹

¹Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, ²Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida 33612, ³International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy, and ⁴Division of Regenerative Medicine, University of Manchester, Manchester M13 9PT, United Kingdom

Correspondence should be addressed to Dr. Leonard Petrucelli, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Email: petrucelli.leonard{at}mayo.edu

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.

Key words: caspase; apoptosis; frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U); amyotrophic lateral sclerosis (ALS); TDP-43; progranulin

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Received July 27, 2007; revised Aug. 15, 2007; accepted Aug. 15, 2007.

Correspondence should be addressed to Dr. Leonard Petrucelli, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Email: petrucelli.leonard{at}mayo.edu

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