CFR Researchers Report Specific Defects in Frontotemporal Dementia Neurons

SAN FRANCISCO, CA - 11/1/12. CFR investigators recently reported specific neuronal deficits in cells from frontotemporal dementia patients. Led by postdoctoral fellow Dr. Sandra Almeida in the lab of senior author and CFR Investigator Dr. Fen-Biao Gao at the University of Massachusetts Medical School, this new study described the establishment of the first patient-specific neuronal models of both progranulin deficiency and sporadic frontotemporal dementia.

Working together with a team including CFR Researchers Drs. Bob Farese and Bruce Miller, Dr. Almeida generated induced pluripotent stem cells from skin cells of two frontotemporal dementia patients and an unaffected control subject. Induced pluripotent stem cells are artificially altered cells that can differentiate into any cell type in the body if given the appropriate molecular instructions. For his discovery of how to make induced pluripotent stem cells, Gladstone Senior Investigator Dr. Shinya Yamanaka, who advised the early design of this study, was awarded the 2012 Nobel Prize in Medicine.

This revolutionary technique allowed Dr. Almeida and colleagues to generate and intensively study live human brain cell types which are affected by frontotemporal dementia but which would otherwise be very difficult to obtain from living patients – in particular, neurons and microglia. Dr. Almeida said, “We generated the first patient-specific neuronal models of frontotemporal dementia, giving us the unprecedented opportunity to analyze this disease in the context of the appropriate living cells.”

One frontotemporal dementia patient carried a novel mutation, S116X, in the progranulin gene that resulted in production of less than 50% of the normal amount of progranulin and causes frontotemporal dementia. The other patient exhibited sporadic frontotemporal dementia, with no mutations detected in known frontotemporal dementia genes. Interestingly, despite their differing genetic backgrounds, derived neurons from both patients showed enhanced sensitivity to chemicals that cause a specific type of cellular stress called ER stress when compared to neurons derived from an unaffected control subject. ER stress, which has also been noted in other neurodegenerative diseases, is caused by an accumulation of unfolded or misfolded proteins and cells experiencing ER stress mount a corrective cellular response.

More importantly, the authors also showed that progranulin-deficient neurons exhibited an increased sensitivity to several kinase inhibitors specific to some important signaling pathways. In particular, the ribosomal protein S6 kinase beta-2 (S6K2) was specifically downregulated. Both cellular phenotypes could be rescued by ectopic progranulin expression in patient neurons. Thus, these studies reveal specific reversible cellular phenotypes in patient neurons.

Dr. Gao proposed, “We believe that chronic weakening of protective pathways caused by progranulin deficiency may result in neurons that are more sensitive in cellular insults, ultimately leading to frontotemporal dementia.”

This study, which was partially supported by The Consortium for FTD Research, was reported in the October 25th edition of Cell Reports.