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G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson’s Disease Patients
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- 38 p.-8 fig.<br />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.<br />This work has been supported by grants from Ministerio de Economía y Competitividad (SAF2011-28603) and Fundación Ramón Areces to AMR, and Fundación Neurociencias y Envejecimiento to JAM.
- Subjects :
- Time Factors
Cell cycle checkpoint
Parkinson's disease
CDK6
TDP-43
PD-332991
Pyridines
Neuroscience (miscellaneous)
Cell Cycle Proteins
Cell cycle
Piperazines
S Phase
Cellular and Molecular Neuroscience
Cyclin-dependent kinase
medicine
Humans
Rapamycin
Lymphocytes
RNA, Messenger
Cyclin D3
Phosphorylation
Kinase activity
Aged
Cell Proliferation
Aged, 80 and over
Sirolimus
biology
Cell growth
G1 Phase
Sodium butyrate
Parkinson Disease
Cell Cycle Checkpoints
Middle Aged
medicine.disease
Cyclin-Dependent Kinases
Parkinson disease
DNA-Binding Proteins
pRb
Neurology
Case-Control Studies
Proteolysis
biology.protein
Cancer research
Butyric Acid
Cyclin-dependent kinase 6
Subcellular Fractions
Subjects
Details
- ISSN :
- 15591182 and 08937648
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Molecular Neurobiology
- Accession number :
- edsair.doi.dedup.....7aa0dcc49ba31c208c2cc1017c26c8ac