title: G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson's Disease Patients.
abstract: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among aging individuals, affecting greatly the quality of their life. However, the pathogenesis of Parkinson's disease is still incompletely understood to date. Increasing experimental evidence suggests that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Since cell cycle dysfunction is not restricted to neurons, we investigated this issue in peripheral cells from patients suffering from sporadic PD and age-matched control individuals. Here, we describe increased cell cycle activity in immortalized lymphocytes from PD patients that is associated to enhanced activity of the cyclin D3/CDK6 complex, resulting in higher phosphorylation of the pRb family protein and thus, in a G1/S regulatory failure. Decreased degradation of cyclin D3, together with increased p21 degradation, as well as elevated levels of CDK6 mRNA and protein were found in PD lymphoblasts. Inhibitors of cyclin D3/CDK6 activity like sodium butyrate, PD-332991, and rapamycin were able to restore the response of PD cells to serum stimulation. We conclude that lymphoblasts from PD patients are a suitable model to investigate cell biochemical aspects of this disease. It is suggested that cyclin D3/CDK6-associated kinase activity could be potentially a novel therapeutic target for the treatment of PD.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Esteras
authors.forename: Carolina
authors.initials: C
authors.lastname: Alquézar
authors.forename: Fernando
authors.initials: F
authors.lastname: Bartolomé
authors.forename: Ana
authors.initials: A
authors.lastname: de la Encarnación
authors.forename: Félix
authors.initials: F
authors.lastname: Bermejo-Pareja
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Molina
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Martín-Requero
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020148:Butyric Acid / Q000494:pharmacology; D016022:Case-Control Studies; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010879:Piperazines; D011725:Pyridines; D012333:RNA, Messenger; D020148:Butyric Acid; D018844:Cyclin-Dependent Kinases; C500026:palbociclib; D020123:Sirolimus