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Forever young: induced pluripotent stem cells as models of inherited arrhythmias
Park, David S; Fishman, Glenn I
PMCID:3630473
PMID: 22647977
ISSN: 0009-7322
CID: 170424
The cardiac conduction system
Park, David S; Fishman, Glenn I
PMCID:3064561
PMID: 21357845
ISSN: 1524-4539
CID: 129007
Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease
Qu, Dianbo; Rashidian, Juliet; Mount, Matthew P; Aleyasin, Hossein; Parsanejad, Mohammad; Lira, Arman; Haque, Emdadul; Zhang, Yi; Callaghan, Steve; Daigle, Mireille; Rousseaux, Maxime W C; Slack, Ruth S; Albert, Paul R; Vincent, Inez; Woulfe, John M; Park, David S
We reported previously that calpain-mediated Cdk5 activation is critical for mitochondrial toxin-induced dopaminergic death. Here, we report a target that mediates this loss. Prx2, an antioxidant enzyme, binds Cdk5/p35. Prx2 is phosphorylated at T89 in neurons treated with MPP+ and/or MPTP in animals in a calpain/Cdk5/p35-dependent manner. This phosphorylation reduces Prx2 peroxidase activity. Consistent with this, p35-/- neurons show reduced oxidative stress upon MPP+ treatment. Expression of Prx2 and Prx2T89A, but not the phosphorylation mimic Prx2T89E, protects cultured and adult neurons following mitochondrial insult. Finally, downregulation of Prx2 increases oxidative stress and sensitivity to MPP+. We propose a mechanistic model by which mitochondrial toxin leads to calpain-mediated Cdk5 activation, reduced Prx2 activity, and decreased capacity to eliminate ROS. Importantly, increased Prx2 phosphorylation also occurs in nigral neurons from postmortem tissue from Parkinson's disease patients when compared to control, suggesting the relevance of this pathway in the human condition.
PMID: 17610816
ISSN: 0896-6273
CID: 2982752
Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death
O'Hare, Michael J; Kushwaha, Neena; Zhang, Yi; Aleyasin, Hossein; Callaghan, Steven M; Slack, Ruth S; Albert, Paul R; Vincent, Inez; Park, David S
Cyclin-dependent kinase 5 (cdk5) is a member of the cyclin-dependent kinase family whose activity is localized mainly to postmitotic neurons attributable to the selective expression of its activating partners p35 and p39. Deregulation of cdk5, as a result of calpain cleavage of p35 to a smaller p25 form, has been suggested to be a central component of neuronal death underlying numerous neurodegenerative diseases. However, the relevance of cdk5 in apoptotic death that relies on the mitochondrial pathway is unknown. Furthermore, evidence that cdk5 can also promote neuronal survival has necessitated a more complex understanding of cdk5 in the control of neuronal fate. Here we explore each of these issues using apoptotic and excitotoxic death models. We find that apoptotic death induced by the DNA-damaging agent camptothecin is associated with early transcription-mediated loss of p35 and with late production of p25 that is dependent on Bax, Apaf1, and caspases. In contrast, during excitotoxic death induced by glutamate, neurons rapidly produce p25 independent of the mitochondrial pathway. Analysis of the localization of p35 and p25 revealed that p35 is mainly cytoplasmic, whereas p25 accumulates selectively in the nucleus. By targeting a dominant-negative cdk5 to either the cytoplasm or nucleus, we show that cdk5 has a death-promoting activity within the nucleus and that this activity is required in excitotoxic death but not apoptotic death. Moreover, we also find that cdk5 contributes to pro-survival signaling selectively within the cytoplasm, and manipulation of this signal can modify death induced by both excitotoxicity and DNA damage.
PMID: 16192386
ISSN: 1529-2401
CID: 2982102
MR imaging of caveolin gene-specific alterations in right ventricular wall thickness
De Souza, Andrea Pereira; Cohen, Alex W; Park, David S; Woodman, Scott E; Tang, Baiyu; Gutstein, David E; Factor, Stephen M; Tanowitz, Herbert B; Lisanti, Michael P; Jelicks, Linda A
Caveolin-1 and caveolin-3 are expressed in the mammalian heart. Mice deficient in caveolin 1 or 3 exhibit cardiac abnormalities including left ventricular hypertrophy and reduced fractional shortening. Cardiac imaging technologies such as transthoracic echocardiography and cardiac-gated magnetic resonance imaging (MRI) are effective tools for the study of left ventricular morphology and function in mice; however, there has not been widespread use of these technologies in studies of right ventricular morphology. In particular, right ventricular wall thickness has been difficult to assess using cardiac imaging technologies. We report here the use of centerline analysis of cardiac-gated MR images to more accurately determine right ventricular wall thickness in the mouse heart. Right ventricular wall thickness was evaluated in Cav-1 null, Cav-3 null and Cav-1/3 null mice, as well as wild-type control mice. Using this technique, we find that caveolin null mice exhibit significant thickening of the right ventricular wall as compared with age-matched wild-type controls. Interestingly, right ventricular wall thickening is greatest in the Cav-1/3 null mice. Furthermore, significant right ventricular wall thickening is also seen in the Cav-1 null mice. Histological analyses revealed right ventricular hypertrophy consistent with the imaging results. These studies demonstrate the utility of MRI in determining right ventricular wall thickness and underscore the severity of the right ventricular hypertrophy in caveolin null mice
PMID: 15733789
ISSN: 0730-725x
CID: 60891
Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins
Bonuccelli, Gloria; Sotgia, Federica; Schubert, William; Park, David S; Frank, Philippe G; Woodman, Scott E; Insabato, Luigi; Cammer, Michael; Minetti, Carlo; Lisanti, Michael P
Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the well-characterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, beta-dystroglycan, alpha-dystroglycan, and alpha-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Thus, the current study opens new and important avenues in our understanding of the pathogenesis of DMD. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.
PMCID:1868305
PMID: 14507673
ISSN: 0002-9440
CID: 1353402