J. Neurochem. (2010) 115, 735–747.

Null mutations in progranulin (GRN) are associated with frontotemporal lobar degeneration characterized by intraneuronal accumulation of TAR DNA‐binding protein‐43 (TDP‐43). However, the mechanism by which GRN deficiency leads to neurodegeneration remains largely unknown. In primary cortical neurons derived from Grn knockout (Grn^−/−) mice, we found that Grn‐deficiency causes significantly reduced neuronal survival and increased caspase‐mediated apoptosis, which was not observed in primary mouse embryonic fibroblasts derived from Grn^−/− mice. Also, neurons derived from Grn^−/− mice showed an increased amount of pTDP‐43 accumulations. Furthermore, proteasomal inhibition with MG132 caused increased caspase‐mediated TDP‐43 fragmentation and accumulation of detergent‐insoluble 35‐ and 25‐kDa C‐terminal fragments in Grn^−/− neurons and mouse embryonic fibroblasts. Interestingly, full‐length TDP‐43 also accumulated in the detergent‐insoluble fraction, and caspase‐inhibition prevented MG132‐induced generation of TDP‐43 C‐terminal fragments but did not block the pathological conversion of full‐length TDP‐43 from soluble to insoluble species. These data suggest that GRN functions as a survival factor for cortical neurons and GRN‐deficiency causes increased susceptibility to cellular stress. This leads to increased aggregation and accumulation of full‐length TDP‐43 along with its C‐terminal derivatives by both caspase‐dependent and independent mechanisms.