Frontotemporal lobar degeneration through loss of progranulin function

Abstract

The striking clinical and pathological features of frontotemporal lobar degeneration (FTLD) have attracted much attention ever since Arnold Pick reported the first disease cases and Alois Alzheimer described the characteristic nerve cell inclusions of Pick's disease. We now know that FTLD is a common cause of dementia, especially in the population below the age of 65 (Neary et al ., 2005). Clinically, it encompasses cases of frontotemporal dementia (FTD), semantic dementia (SD) and primary progressive aphasia (PPA). Of these, FTD is the most common. It is characterized by progressive behavioural and personality disturbances, which evolve gradually into cognitive impairment and dementia. SD is characterized by a loss of conceptual knowledge, whereas in PPA progressive language impairment usually precedes the behavioural symptoms. In some patients, behavioural symptoms are also associated with a parkinsonian syndrome or with motor neuron disease (MND). Pathologically, FTLD is characterized by the severe degeneration of frontal and/or temporal regions of the cerebral cortex. It can be divided into three broad subtypes, based on the presence of abnormal inclusions inside nerve cells. Filamentous cytoplasmic inclusions made of hyperphosphorylated tau protein characterize a proportion of cases with FTLD, including Pick's disease (Spillantini et al ., 1998). In recent years, it has become apparent that a substantial number of disease cases is characterized by the presence of tau-negative, ubiquitin-positive inclusions (FTLD-U) (Hodges et al ., 2004). The third subtype, FTLD lacking distinctive histopathology, where abnormal inclusions are not observed, now appears to be much less common than believed previously (Mackenzie et al ., 2006 a ). FTLD has a substantial genetic component, in that up to 40% of cases are inherited in a dominant manner (Rosso et al ., 2003). Several disease loci and genes have been identified on chromosomes 3, 9 and 17. Mutations in the Tau gene on …