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Inactivation of CDK6/pRb pathway normalizes survival pattern of lymphoblasts expressin the FTLD-TDP-Progranulin mutation c.709-1G>A.

AuthorsAlquézar, Carolina ; Esteras, Noemí ; Alzualde, Ainhoa; Moreno, Fermín; Sánchez Ayuso, Matilde ; López de Munain, Adolfo; Martín-Requero, Ángeles
Issue Date18-May-2012
PublisherPublic Library of Science
CitationPLoS ONE 7(5):e37057(2012)
AbstractBackground 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
Description8 figuras, 2 tablas
Publisher version (URL)http://dx.doi.org/ 10.1371/journal.pone.0037057
Appears in Collections:(CIB) Artículos
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