2024-03-29T10:06:19Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/500692021-12-27T16:35:06Zcom_10261_86com_10261_1col_10261_339
00925njm 22002777a 4500
dc
Alquézar, Carolina
author
Esteras, Noemí
author
Alzualde, Ainhoa
author
Moreno, Fermín
author
Sánchez Ayuso, Matilde
author
López de Munain, Adolfo
author
Martín-Requero, Ángeles
author
2012-05-18
Background
Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation.
Methodology/Principal Findings
We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal.
Conclusion/Significance
The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP
PLoS ONE 7(5):e37057(2012)
1932-6203
http://hdl.handle.net/10261/50069
10.1371/journal.pone.0037057
1932-6203
22623979
Inactivation of CDK6/pRb pathway normalizes survival pattern of lymphoblasts expressin the FTLD-TDP-Progranulin mutation c.709-1G>A.