Year 1

In this grant, we proposed to generate induced pluripotent stem (iPS) cells from skin cells derived from human subjects with frontotemporal dementia (FTD). FTD accounts for 15–20% of all dementia cases and, with newly identified genetic causes, is now recognized as the most common dementia in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal and temporal lobes and other brain regions, resulting in behavioral changes and memory and motor neuron deficits. The median age of onset of this devastating disease is 58 years, and it progresses rapidly, causing death in 3–8 years. Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD are poorly understood. Genetic causes are estimated to account for ~40% of FTD. In addition to tau identified in 1998, mutations in three causative genes have been identified during the last three years. The identification of FTD mutations opens exciting new avenues for understanding the causes of FTD. Research on these mutations will help to identify effective therapies. However, the ability to study the functions of these factors is severely limited due to the lack of available human neurons from FTD patients. To address the need for disease– and patient–specific neurons, we proposed to use the powerful new technique of iPS cells. iPS cells are derived from skin cells and can be used to generate any cell types in the body, including neurons. During the last 10 months, we have obtained human skin cells from more than 30 FTD patients with disease-causing mutations and unaffected family members. We have generated about 200 putative iPS cell lines from two FTD patients with defined genetic mutations, one sporadic case, and one control. We characterized some of the iPS cell lines and differentiated one patient-specific iPS cell line into human postmitotic neurons. These results represent a major advance toward finding a cure for FTD, and we will continue to pursue this line of research as proposed.