PMID- 25689470
OWN - NLM
STAT- MEDLINE
DCOM- 20150902
LR  - 20150610
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 133
IP  - 6
DP  - 2015 Jun
TI  - Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease.
PG  - 886-97
LID - 10.1111/jnc.13070 [doi]
AB  - At present, treatment for Parkinson's disease (PD) is only symptomatic; 
      therefore, it is important to identify new targets tackling the molecular causes 
      of the disease. We previously found that lymphoblasts from sporadic PD patients 
      display increased activity of the cyclin D3/CDK6/pRb pathway and higher 
      proliferation than control cells. These features were considered systemic 
      manifestations of the disease, as aberrant activation of the cell cycle is 
      involved in neuronal apoptosis. The main goal of this work was to elucidate 
      whether the inhibition of cyclin D3/CDK6-associated kinase activity could be 
      useful in PD treatment. For this purpose, we investigated the effects of two 
      histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic (SAHA) acid and 
      sodium butyrate (NaB), and the m-TOR inhibitor rapamycin on cell viability and 
      cyclin D3/CDK6 activity. Moreover, the potential neuroprotective action of these 
      drugs was evaluated in 6-hydroxy-dopamine (6-OHDA) treated dopaminergic SH-SY5Y 
      cells and primary rat mesencephalic cultures. Here, we report that both compounds 
      normalized the proliferative activity of PD lymphoblasts and reduced the 
      6-OHDA-induced cell death in neuronal cells by preventing the over-activation of 
      the cyclin D3/CDK6/pRb cascade. Considering that these drugs are already used in 
      clinic for treatment of other diseases with good tolerance, it is plausible that 
      they may serve as novel therapeutic drugs for PD. We report here that peripheral 
      cells from Parkinson's disease (PD) patients show an enhanced proliferative 
      activity due to the activation of cyclin D3/CDK6-mediated phosphorylation of 
      retinoblastoma protein (pRb). Treatment of PD lymphoblasts with inhibitors of 
      histone deacetylases like suberoylanilide hydroxamic acid (SAHA) and sodium 
      butyrate (NaB), or with rapamycin, inhibitor of mechanistic target of rapamycin 
      (mTOR) normalized the proliferation of PD lymphoblasts by preventing the 
      over-activation of the cyclin D3/CDK6/pRb cascade. These drugs were shown to have 
      neuroprotective effects in both human neuroblastoma SH-SY5Y cells and primary rat 
      mid-brain dopaminergic neuronal cultures toxicity induced by 6-hidroxydopamine. 
      Considering that these drugs are already used in clinic for treatment of other 
      diseases with good tolerance, it seems reasonable to believe that the 
      repositioning of these drugs toward PD holds promise as a novel therapeutic 
      strategy.
CI  - (c) 2015 International Society for Neurochemistry.
FAU - Alquezar, Carolina
AU  - Alquezar C
AD  - Department of Cellular and Molecular Medicine, Centro de Investigaciones 
      Biologicas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, 
      Spain.
FAU - Barrio, Estibaliz
AU  - Barrio E
AD  - Department of Cellular and Molecular Medicine, Centro de Investigaciones 
      Biologicas (CSIC), Madrid, Spain.
FAU - Esteras, Noemi
AU  - Esteras N
AD  - Department of Cellular and Molecular Medicine, Centro de Investigaciones 
      Biologicas (CSIC), Madrid, Spain.
FAU - de la Encarnacion, Ana
AU  - de la Encarnacion A
AD  - Department of Cellular and Molecular Medicine, Centro de Investigaciones 
      Biologicas (CSIC), Madrid, Spain.
FAU - Bartolome, Fernando
AU  - Bartolome F
AD  - Neuroscience Laboratory, Research Institute, Hospital Doce de Octubre, Madrid, 
      Spain.
FAU - Molina, Jose A
AU  - Molina JA
AD  - Department of Neurology, Hospital Doce de Octubre, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas 
      (CIBERNED), Madrid, Spain.
FAU - Martin-Requero, Angeles
AU  - Martin-Requero A
AD  - Department of Cellular and Molecular Medicine, Centro de Investigaciones 
      Biologicas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, 
      Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150315
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Cyclin D3)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Neuroprotective Agents)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cyclin D3/*antagonists & inhibitors
MH  - Cyclin-Dependent Kinase 6/*antagonists & inhibitors
MH  - Female
MH  - Histone Deacetylase Inhibitors/pharmacology
MH  - Humans
MH  - Immunoblotting
MH  - Lymphocytes/drug effects/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neurons/drug effects/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Parkinson Disease/*metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Real-Time Polymerase Chain Reaction
OTO - NOTNLM
OT  - Parkinson's disease
OT  - cyclin D3/CDK6
OT  - pRb
OT  - rapamycin
OT  - sodium butyrate
OT  - suberoylanilide hydroxamic acid
EDAT- 2015/02/18 06:00
MHDA- 2015/09/04 06:00
CRDT- 2015/02/18 06:00
PHST- 2014/10/23 00:00 [received]
PHST- 2015/02/10 00:00 [revised]
PHST- 2015/02/10 00:00 [accepted]
PHST- 2015/02/18 06:00 [entrez]
PHST- 2015/02/18 06:00 [pubmed]
PHST- 2015/09/04 06:00 [medline]
AID - 10.1111/jnc.13070 [doi]
PST - ppublish
SO  - J Neurochem. 2015 Jun;133(6):886-97. doi: 10.1111/jnc.13070. Epub 2015 Mar 15.