Frontotemporal lobar degeneration (FTLD) is the second most common form of early-onset dementia after Alzheimer's disease (AD), accounting for 5-10 percent of all dementia patients and 10-20 percent of patients with an onset of dementia before 65 years. Up to 50 percent of FTLD patients report a family history of dementia, suggesting a strong genetic component to the disease. FTLD usually affects patients in midlife, but onset of symptoms can vary between the age of 35 and 75 years. The most common clinical manifestation of FTLD is frontotemporal dementia (FTD), whereby patients present with an early alteration in personality and social conduct, characterized by inertia, loss of volition, and disinhibition, followed by more general cognitive decline, eventually leading to dementia. Sometimes, FTD is accompanied by signs of parkinsonism or by amyotrophic lateral sclerosis (FTD-ALS). The neuropathology associated with most FTD patients is characterized by atrophy of the frontal and temporal lobes and the presence of abnormal intracellular protein aggregates of the tau protein (FTLD-tau) or the TAR DNA-binding protein 43 (FTLD-TDP).
As expected from the clinical and pathologic heterogeneity, the molecular genetics of FTLD are complex. To date, 4 FTLD genes have already been identified and one confirmed genetic locus for FTLD has been reported on chromosome 9p. Mutations in the microtubule associated protein tau (MAPT) gene on chromosome 17q21 were identified in patients with tau-positive FTLD and we are others recently identified mutations in the secreted growth factor progranulin (GRN) as an important cause of FTLD with TDP-43 pathology. Importantly, together the known genes explain the disease in less than half of the familial FTLD patients and in a minority of the apparently sporadic FTLD patients, suggesting that additional genes and genetic risk factors are involved.
While there are currently no treatments to slow or stop the progression of FTLD, the identification of mutations in MAPT and GRN yielded an important understanding of the pathogenic mechanisms underlying FTLD and enabled the generation of the first transgenic models for this disease. The research in our laboratory is focused on the identification of novel causal genes and genetic risk factors for FTLD and related disorders to provide additional insight into these diseases. In addition, we aim to better understand the regulation of GRN with the goal to identify novel molecular targets for FTLD therapy.