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- W2079607780 endingPage "403" @default.
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- W2079607780 abstract "Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder marked by mild-life onset and progressive changes in behavior, social cognition, and language. Loss-of-function progranulin gene (GRN) mutations are the major cause of FTLD with TDP-43 protein inclusions (FTLD-TDP). Disease-modifying treatments for FTLD-TDP are not available yet. Mounting evidence indicates that cell cycle dysfunction may play a pathogenic role in neurodegenerative disorders including FTLD. Since cell cycle re-entry of posmitotic neurons seems to precede neuronal death, it was hypothesized that strategies aimed at preventing cell cycle progression would have neuroprotective effects. Recent research in our laboratory revealed cell cycle alterations in lymphoblasts from FTLD-TDP patients carrying a null GRN mutation, and in PGRN deficient SH-SY5Y neuroblastoma cells, involving overactivation of the ERK1/2 signaling pathway. In this work, we have investigated the effects of PGRN enhancers drugs and ERK1/2 inhibitors, in these cellular models of PGRN-deficient FTLD. We report here that both restoring the PGRN content, by suberoylanilide hydroxamic acid (SAHA) or chloroquine (CQ), as blocking ERK1/2 activation by selumetinib (AZD6244) or MEK162 (ARRY-162), normalized the CDK6/pRb pathway and the proliferative activity of PGRN deficient cells. Moreover, we found that SAHA and selumetinib prevented the cytosolic TDP-43 accumulation in PGRN-deficient lymphoblasts. Considering that these drugs are able to cross the blood-brain barrier, and assuming that the alterations in cell cycle and signaling observed in lymphoblasts from FTLD patients could be peripheral signs of the disease, our results suggest that these treatments may serve as novel therapeutic drugs for FTLD associated to GRN mutations." @default.
- W2079607780 created "2016-06-24" @default.
- W2079607780 creator A5003591572 @default.
- W2079607780 creator A5038020678 @default.
- W2079607780 creator A5051076620 @default.
- W2079607780 creator A5051878993 @default.
- W2079607780 creator A5086774103 @default.
- W2079607780 creator A5091067891 @default.
- W2079607780 date "2015-03-01" @default.
- W2079607780 modified "2023-10-18" @default.
- W2079607780 title "Increasing progranulin levels and blockade of the ERK1/2 pathway: Upstream and downstream strategies for the treatment of progranulin deficient frontotemporal dementia" @default.
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- W2079607780 doi "https://doi.org/10.1016/j.euroneuro.2014.12.007" @default.