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

卷:33

Article

Alquezar, Carolina¹  Esteras, Noemi¹  Bartolome, Fernando¹  Merino, Jose J.^2,3  Alzualde, Ainhoa^2,3  Lopez de Munain, Adolfo^2,3  Martin-Requero, Angeles¹ 

[1] CSIC, Ctr Invest Biol, Dept Cellular & Mol Med, Madrid 28040, Spain

[2] Hosp Donostia, Inst Biodonostia, Dept Neurol, San Sebastian, Spain

[3] Hosp Donostia, Inst Biodonostia, Expt Unit, San Sebastian, Spain

关键词: FTLD;    Lymphocytes;    Cell cycle;    pRb;    CDK6;    TDP-43;   

DOI  :  10.1016/j.neurobiolaging.2010.11.020

来源: Elsevier

【 摘 要 】

Frontotemporal 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. (C) 2012 Elsevier Inc. All rights reserved.

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