Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures.

Null mutations in the progranulin gene (PGRN) have been identified as a major cause of frontotemporal dementia with ubiquitinated inclusions. In this disorder, ubiquitinated, aggregated protein inclusions of a normally nuclear-located RNA processing protein called TAR DNA binding protein (TDP-43) accumulate in the neuronal cytoplasm (FTLD-TDP). To determine whether aspects of this clinical pathology can be established in primary cultures of mouse cortical neurons, PGRN levels were knocked down in neuronal cultures using lentiviral vectors to introduce mouse PGRN-siRNA constructs and subsequently rescued by overexpressing PGRN using a human PGRN-expressing lentiviral vector. The depletion of PGRN enhanced caspase-3 activation, and the PGRN-deficient neurons demonstrated enhanced vulnerability to normally sublethal doses of N-methyl-D-aspartic acid (NMDA) and hydrogen peroxide (H(2)O(2)). TDP-43 protein levels were markedly increased in the cytoplasm of PGRN-deficient neurons relative to nuclear levels, which is similar to observations in the brains of FTLD-TDP patients. Our results establish a neuronal culture model of the PGRN deficiency, which displays some of the important phenotypic characteristics of the early stages of the disease. The results further suggest that the seeds of this form of frontotemporal dementia may be sown early in life.