Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in those under the age of 65. Mutations in the human progranulin (PGRN) gene have recently been shown to be causal for both inherited and sporadic forms of FTLD (Baker et al., 2006, Hutton et al., 2006). Progranulin is a complex, multifunctional, secreted trophic factor that is expressed in a variety of tissues including neurons and astrocytes (Ahmed et al., 2007). Although PGRN is involved in development, wound healing, inflammation and tumor growth, its function in the nervous system is poorly understood (Eriksen and Mackenzie, 2008). In order to better understand the biological function of progranulin, we decided to study its homolog in C. elegans. Similar to the mammalian protein, the C. elegans progranulin homolog, PGRN-1, is expressed by the intestine and a subset of neurons.
pgrn-1 mutant worms appear grossly normal and live a normal lifespan compared to control worms. However, we have found that
pgrn-1 mutants have a decreased number of programmed cell deaths during development. In addition, young adult
pgrn-1 mutants display resistance to osmotic, thermal and ER stress compared to wild-type worms while older worms are sensitive to osmotic stress. The stress resistance phenotype can be rescued by expression of either worm or human progranulin. We are currently examining whether these constructs also rescue the cell death phenotype. Unlike mutations in the insulin-IGF-1 receptor gene,
daf-2,
pgrn-1 mutations do not cause resistance to genotoxic or oxidative stress, suggesting a novel pathway for selective stress resistance. This dichotomous response to certain stressors-resistance while young and increased susceptibility with age-may shed light on why individuals with progranulin mutations develop FTLD symptoms late in adulthood and may explain the variable age of disease onset seen with identical mutations. Interestingly, our findings suggest that susceptibility to neurodegeneration may be determined during a developmental period when excess or unneeded neurons undergo programmed cell death.