Abstract
Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in the induced pluripotent stem-cell-derived neurons (iPSN) from two sporadic bvFTD patients and one normal subject. We also used an FTD-patient-derived iPSC-line-carrying microtubule-associated protein tau (MAPT) P301L point mutation as positive control for p-Tau expression. Staurosporine (STS) was used to induce cellular stress in order to investigate dynamic cellular responses related to the cell death pathway. As a result, the expression of active caspase-3 was highly increased in the bvFTD-iPSNs compared with control iPSNs in the STS-treated conditions. Other cell-death-related proteins, including Bcl-2-associated X protein (Bax)/Bcl-2 and cytochrome C, were also increased in the bvFTD-iPSNs. Moreover, we observed abnormal expression patterns of TDP-43 and FUS in the bvFTD-iPSNs compared with control iPSNs. We suggest that the iPSC technology might serve as a potential tool to demonstrate neurodegenerative phenotypes of bvFTD, which will be useful for studying pathological mechanisms for FTD as well as related drug screening in the future.
Highlights
Frontotemporal dementia (FTD) is the second-most common cause of neurodegenerative dementia, showing behavioral problems typically in people younger than 65 years of age [1,2]
Genetic mutations linked to FTD include microtubule-associated protein tau (MAPT), progranulin (PGRN), and chromosome 9 open reading frame 72 (C9orf72) [7], which have been targeted for studying pathological mechanism or discovering new treatments
These results strongly suggest that Behavioral variant FTD (bvFTD)-induced pluripotent stem-cell-derived neurons (iPSN) exhibit higher vulnerability to cell death under cellular stress condition, compared with controls. Both immunoblot and immunocytochemistry results showed no significant differences in the expression level of cleaved caspase-3 between the normal control and positive control carrying MAPT P301L mutation (Figure 3B,G). These results strongly suggest bvFTD-iPSNs are highly vulnerable to cell death under cellular stress condition, and the level of cleaved caspase-3 can be utilized as a useful biomarker when these cells are used for drug screening
Summary
Frontotemporal dementia (FTD) is the second-most common cause of neurodegenerative dementia, showing behavioral problems typically in people younger than 65 years of age [1,2] Most importantly, it prominently features atrophy in the frontal and temporal lobes leading to frontotemporal lobar degeneration (FTLD) associated with a wide range of heterogeneous pathologies. We generated patient-specific iPSC lines from two young sporadic bvFTD patients using their peripheral blood mononuclear cells (PBMCs) and characterized their neurons (bvFTD-iPSNs) with respect to the expression level of FTD-tau, TDP-43, FUS, and activated caspase-3. Immunocytochemical and immunoblot analyses indicated that the active caspase-3 expression, indicative of neurodegenerative feature, was significantly increased compared with controls This neurodegenerative feature of FTD can be used as a useful marker for studying pathological mechanisms, as well as drug screening
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