EDITOR'S PICK: Lessons from yeast: a possible cure for Parkinson Disease?
Parkinson disease (PD) is a debilitating and lethal neurodegenerative disease, for which there is currently no cure. It is caused by the progressive loss of nerve cells that produce the chemical dopamine and is characterized by the accumulation of abnormal aggregates of a protein called alpha-syn in these dopaminergic nerve cells. Several previous studies have suggested that the alpha-syn aggregates contribute to PD pathology, so it is possible that an agent that inhibits and/or, better yet, reverses alpha-syn aggregation could be eventually used as a therapy for PD. Evidence to suggest that agents that disrupt alpha-syn aggregation might have beneficial effects in individuals with PD has now been provided by a team of researchers, at the Ecole Polytechnique Fédérale de Lausanne, Switzerland, and the University of Pennsylvania School of Medicine, Philadelphia, who studied a rat model of the disease.
In the study, it was found that a protein that yeast uses to protect itself from protein aggregation (there is no similar protein in mammals), called Hsp104, dramatically reduced both the formation of alpha-syn aggregates and the degeneration of neurons in the brain in a rat mdoel of PD. In vitro studies showed that Hsp104 not only inhibited alpha-syn aggregate formation, but also interacted with mammalian proteins to disassemble them. The authors therefore suggest that Hsp104 should be considered as a potential strategy for the treatment of individuals with PD, after further studies on the safety of introducing Hsp104 into the brain.
TITLE: Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease
AUTHOR CONTACT:
Patrick AebischerEcole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.Phone: 41-21-693-9505; Fax: 41-21-693-9510; E-mail: patrick.aebischer@epfl.ch.
James ShorterUniversity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. Phone: (215) 573-4256; Fax: (215) 573-4764; E-mail: jshorter@mail.med.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35781
HEMATOLOGY: Inhibitors of the molecule PI3K throw one form of leukemia a curveB-ALL
Some cases of a form of leukemia known as pre–B cell acute lymphoblastic leukemia (pre–B-ALL) are caused by a genetic event that leads to the generation of a rogue chromosome known as the Philadelphia (Ph) chomosome, and individuals with Ph+ pre–B-ALL tend to have a poor outlook. As current treatments for Ph+ pre–B-ALL are not very effective, researchers are looking for new drugs to combat this disease. And now, David Fruman and colleagues, at the University of California, at Irvine, have generated data in mice and human cells that might provide insight into a new molecule to target in this clinical setting.
In the study, deletion of two genes responsible for generating a molecule known as PI3K prevented the development of disease in a mouse model of Ph+ pre–B-ALL. Consistent with an important role for PI3K in the development of Ph+ pre–B-ALL, a drug that inhibits PI3K as well as another signaling molecule known as mTOR suppressed the growth of mouse B-ALL and human Ph+ ALL leukemia cells in vitro. The authors therefore suggest that targeting PI3K, either alone or together with mTOR, might prove beneficial to individuals with of Ph+ pre–B-ALL.
TITLE: Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells
AUTHOR CONTACT:David A. FrumanUniversity of California, at Irvine, Irvine, California, USA.Phone: (949) 824-1947; Fax: (949) 824-8551; E-mail: dfruman@uci.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33337
BACTERIOLOGY: Fruit flies provide insight into bacterial infections in humans
Joseph Zabner and colleagues, at the University of Iowa Carver College of Medicine, Iowa City, have used a fruit fly (Drosophila) model of infection to provide new insight into the molecular mechanisms underlying the virulence of the bacterium Pseudomonas aeruginosa, which is a major cause of infections in individuals who are hospitalized, have burn wounds, or have cystic fibrosis.
P. aeruginosa communicate with each other via a process known as quorum sensing. Previous studies have suggested that P. aeruginosa quorum-sensing molecules (such as 3OC12-HSL) are important for virulence and that human proteins known as PONs, which are able to destroy quorum-sensing molecules, contribute to protection from lethal P. aeruginosa infection. For various reasons it has been hard to develop a model system in which to test this hypothesis. So, the authors turned to a Drosophila model of infection, as these flies have no PONs proteins of their own. Initial studies established that P. aeruginosa infection kills Drosophila and that this depends on the ability of the P. aeruginosa to produce 3OC12-HSL. However, if the Drosophila were engineered to express human PON1 they were protected from killing following P. aeruginosa infection. These data indicate that PON1 is important for protection against lethal P. aeruginosa infection via its ability to interfere with quorum sensing, and further suggest that targeting quorum-sensing molecules or modulating PON function might provide new approaches to therapy.
TITLE: Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1
AUTHOR CONTACT:Joseph ZabnerUniversity of Iowa Carver College of Medicine, Iowa City, Iowa, USA.Phone: (319) 335-7608; Fax: (319) 335-7623; E-mail: joseph-zabner@uiowa.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35147
CARDIOLOGY: Beating of the heart: differentially regulated in the upper and lower chambers
Rodolphe Fischmeister and colleagues, at INSERM UMR-S 769, France, have provided evidence that the contraction of the two regions of the heart, the atria and the ventricles, is differentially regulated.
The contraction phase of the heart beat is controlled by several pathways, including one initiated by stimulation of cell surface proteins known as beta-adrenergic receptors. At the molecular level, the flow of Ca2+ through protein channels known as L-type Ca2+ channels has a central role in the regulation of the contraction of the heart by beta-adrenergic receptors. Previous data have indicated that stimulation of beta-3-adrenergic receptor (beta-3-AR) decreases the contractility of tissue from human ventricles (the lower chambers of the heart) and decreases the activity of ventricle L-type Ca2+ channels in various animal models. In contrast, Fischmeister and colleagues have now found that beta-3-AR stimulation increases the activity of L-type Ca2+ channels in heart cells isolated from human atria (the upper chambers of the heart) and increases the contractility of human atrial tissue. This demonstration that beta-3-AR stimulation has opposing effects on human atrial and ventricular tissue has important implications for those developing therapeutics targeting beta-adrenergic receptors for the treatment of cardiovascular diseases.
TITLE: Beta-3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current
AUTHOR CONTACT:Rodolphe FischmeisterINSERM UMR-S 769, Châtenay-Malabry, France.Phone: 33-1-46-83-57-71; Fax: 33-1-46-83-54-75; E-mail: rodolphe.fischmeister@inserm.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32519
ONCOLOGY: Helping tumor cells not to stick to the wound during surgical removal
Sometimes during surgery to remove a tumor, cells become detached from the bulk of the tumor. In a small number of cases, these tumor cells stick to cells at the site of the surgical wound and go on to form a secondary tumor, having an enormous negative impact on the survival and quality of life of the patient. New data, generated by Marc Basson and colleagues, at the John D. Dingell VA Medical Center and Wayne State University, Detroit, using a mouse model of surgery to remove a colon cancer tumor, suggest that perioperative treatment with a drug known as colchicine might decrease the incidence of tumor formation at the site of the surgical wound.
When colon cancer tumor cells are exposed to high pressure they exhibit an increased ability to stick to other cells. In the study, to mimic the conditions of surgery, the authors removed colon cancer cells from one mouse, exposed them to high pressure in vitro, and then transplanted them into a second mouse that they monitored for the development of tumors at the site of the surgical wound. The most important observation made was that if the mice from which the colon cancer cells came from were treated perioperatively with colchicine there was a dramatic decrease in the number of tumors that formed at the site of the surgical wound in the second mouse. As in vitro exposure of tumor cells from breast and head and neck cancers to high pressure also increases their ability to stick to other cells it is possible that these data might have implications in several clinical settings.
TITLE: Colchicine inhibits press-induced tumor cell implantation within surgical wounds and enhances tumor-free survival in mice
AUTHOR CONTACT:Marc D. BassonJohn D. Dingell VA Medical Center and Wayne State University, Detroit, Michigan, USA.Phone: (313) 576-3598; Fax: (313)-576-1002; E-mail: marc.basson@va.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34279
NEUROBIOLOGY: New insight into a fatal childhood neurodegenerative disorder
Infants with the childhood neurodegenerative disorder infantile neuronal ceroid lupofuscinoses (INCL) suffer from seizures and involuntary twitching/jerking of a single muscle or a group of muscles. The disease, which is fatal, is caused by deficiency in the protein PPT1 as a result of mutations in the PPT1 gene. Anil Mukerjee and colleagues, at the National Institutes of Health, Bethesda, have now provided new insight into the molecular mechanisms by which PPT1 deficiency causes INCL through their analysis of both a mouse model of INCL and postmortem brain tissue from an individual with INCL. Specifically, they observed that PPT1 deficiency causes proteins with an essential role in facilitating nerve cell communication to become permanently anchored to the cell membrane. This impaired the ability of nerve cells to release the substances that they use to communicate with other nerve cells and is likely to contribute to the neurological symptoms of INCL.
TITLE: Palmitoyl protein thioesterae-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice
AUTHOR CONTACT:Anil B. MukherjeeNational Institutes of Health, Bethesda, Maryland, USA.Phone: (301) 496-7213; Fax: (301) 402-6632; E-mail: mukherja@exchange.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33482