RT Journal Article
T1 Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia
A1 Alquezar, Carolina
A1 Esteras, Noemí
A1 Bartolomé, Fernando
A1 Merino Martín, José Joaquín
A1 Alzualde, Ainhoa
A1 López de Munain, Adolfo
A1 Martín-Requero, Ángeles
AB AbstractFrontotemporal lobar degeneration with neuronal inclusions containing TAR DNA binding protein 43 (TDP-43) is associated in most cases with null-mutations in the progranulin gene (PGRN). While the mechanisms by which PGRN haploinsufficiency leads to neurodegeneration remained speculative, increasing evidence support the hypothesis that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Based in the mitogenic and neurotrophic activities of PGRN, we hypothesized that PGRN deficit may induce cell cycle disturbances and alterations in neuronal vulnerability. Because cell cycle dysfunction is not restricted to neurons, we studied the influence of PGRN haploinsufficiency, on cell cycle control in peripheral cells from patients suffering from frontotemporal dementia, bearing the PGRN mutation c.709-1G>A. Here we show that progranulin deficit increased cell cycle activity in immortalized lymphocytes. This effect was associated with increased levels of cyclin-dependent kinase 6 (CDK6) and phosphorylation of retinoblastoma protein (pRb), resulting in a G(1)/S regulatory failure. A loss of function of TDP-43 repressing CDK6 expression may result from altered subcellular TDP-43 distribution. The distinct functional features of lymphoblastoid cells from c.709-1 G>A carriers offer an invaluable, noninvasive tool to investigate the etiopathogenesis of frontotemporal lobar degeneration.
PB Elsevier
SN 0197-4580
YR 2010
FD 2010
LK https://hdl.handle.net/20.500.14352/115957
UL https://hdl.handle.net/20.500.14352/115957
LA eng
NO Alquezar, C., Esteras, N., Bartolomé, F., Merino, J. J., Alzualde, A., López de Munain, A., & Martín-Requero, Á. (2012). Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia. Neurobiology of aging, 33(2), . https://doi.org/10.1016/j.neurobiolaging.2010.11.020
NO Fundación Eugenio Rodríguez Pascual
NO Diputación Foral de Gipuzkoa
NO Eusko Jaurlaritza
NO Ministerio de Educación y Ciencia (España)
DS Docta Complutense
RD 6 abr 2025