- Email: [email protected]
Bcl-2 and neuronal cell death
173
Notes
Metabolic
cardioprotection
with ribose.
Although ischaemia has profound consequences for the heart’s energy metabolism, there is no established treatment specifically aimed at influencing or preventing these consequences. This is a major limitation of current treatment. since normal heart function and tissue preservation constantly require large amounts of energy derived from ATP. In the heart, ATP stores are very limited. sufficient for less than I minute of contraction. During ischaemia ATP levels decline rapidly. They do not however recover upon reperfusion and remain depressed for several days because ATP de )ioi~ synthesis in the heart is extremely slow. Long-term postischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Ribose. a pentose sugar. bypasses rate-limiting steps in ATP precursor synthesis and increases ATP restoration by providing the essential precursor PRPP. In a randomized placebo-controlled double-blind study. 20 men with severe coronary artery disease (CAD) and reproducible exercise-induced angina and ST depression. received a 3-day course of oral ribose (60 g per day) or placebo. A treadmill exercise test after treatment showed significant improvement in time to ST depression (P = 0.002 vs placebo) and time to angina in patients in the ribose group. The mean increase in treadmill walking time until ST depression with ribose is equivalent to a rise of more than 309&. The placebo group did not show any significant changes. Ribose was well tolerated and only minor side effects occurred. It is concluded that in patients with CAD. oral administration of ribose improved the heart’s tolerance to ischemia. The presumed effects of ribose on myocardial energy metabolism offer new possibilities for the medical treatment of myocardial ischaemia. Wolfgang Pliml t I) University of Munich. Department of Medicine, Medizinisehe Klinik 1. Klinikum Grosshadem. Munich, Germany
Bcl-2 and neuronal
cell death.
Programmed Cell Death (PCD) or apoptosis occurs in most animal tissues at some stage during their development. Thus, approximately half of the neurons produced during embryogenesis die before adulthood. The number of neurons that die (or survive) seems to be controlled by neurotrophic factors supplied in limiting amounts by the targets cells that neurons innervate. Neurons that fail to get enough trophic factor die apparently by active suicide as, in some cases at least. their death can be prevented by RNA or protein syn( I ) Ltrrrcrr
t 1992)
304,
507
thesis inhibitors. The mechanisms by which trophic factors can interfere with PCD are unknown. Recently, we found that over expression of the Bcl-2 proto-oncogene in cultured sympathetic neurons prevents apoptosis normally induced by deprivation of the trophic factors nerve growth factor (NGF). Bcl-2 is a proto-oncogene that has been isolated from the chromosomal breakpoint of folicular B-cell lymphoma. The gene encodes a mitochondrial membrane protein that was shown primarily to block PCD in B and T lymphocytes. We do not know how Bcl-2 blocks PCD. We suggest that this protein may be a major mediator of the effects of neurotrophic factors on neuronal survival. Understanding the function of Bcl-2 could open new ways to treat diseases caused by too much cell death - Huntington’s disease and Parkinson’s disease for example - or too little cell death as may be the case in some cancers. Glaxo
Institute
JC Martinou (2) for Molecular Biology Geneva, Switzerland
Perixome biogenesis and Pas2 protein. In order to investigate the mechanisms of peroxisome biogenesis, we studied pas-mutants (Peroxisome nssembly) in the yeast Socchumnyes cerevisiae as a eukaryotic model system. These mutants are characterized by the absence of functional peroxisomes. In man, comparable peroxisomal deficiencies result in disorders such as Zellweger syndrome. neonatal adrenoleukodystrophy or infantile Refum disease. The Pas2-gene affected in the pas2-mutant was found to be a member of the family of ubiquitin-conjugating enzymes. These confer specificity of substrate recognition in the ubiquitination cascade, which leads to covalent ligation of ubiquitin to target proteins. The ubiquitination signal has been shown to be involved in a wide variety of cellular processes such as protein degradation, DNA repair, sporulation, and cell cycle control. Our results demonstrate the requirement for a ubiquitin-conjugating enzyme in peroxisome biogenesis. indicating a crucial role of the ubiquitination cascade in organelle formation.
D-4630 (2) Scirrrce (3) Nururc
(1992) (1992)
258. 302 359. 73
FF Wiebel(3) Ruhr-Universitlt. Bochum I, Germany
Notes
Metabolic
cardioprotection
with ribose.
Although ischaemia has profound consequences for the heart’s energy metabolism, there is no established treatment specifically aimed at influencing or preventing these consequences. This is a major limitation of current treatment. since normal heart function and tissue preservation constantly require large amounts of energy derived from ATP. In the heart, ATP stores are very limited. sufficient for less than I minute of contraction. During ischaemia ATP levels decline rapidly. They do not however recover upon reperfusion and remain depressed for several days because ATP de )ioi~ synthesis in the heart is extremely slow. Long-term postischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Ribose. a pentose sugar. bypasses rate-limiting steps in ATP precursor synthesis and increases ATP restoration by providing the essential precursor PRPP. In a randomized placebo-controlled double-blind study. 20 men with severe coronary artery disease (CAD) and reproducible exercise-induced angina and ST depression. received a 3-day course of oral ribose (60 g per day) or placebo. A treadmill exercise test after treatment showed significant improvement in time to ST depression (P = 0.002 vs placebo) and time to angina in patients in the ribose group. The mean increase in treadmill walking time until ST depression with ribose is equivalent to a rise of more than 309&. The placebo group did not show any significant changes. Ribose was well tolerated and only minor side effects occurred. It is concluded that in patients with CAD. oral administration of ribose improved the heart’s tolerance to ischemia. The presumed effects of ribose on myocardial energy metabolism offer new possibilities for the medical treatment of myocardial ischaemia. Wolfgang Pliml t I) University of Munich. Department of Medicine, Medizinisehe Klinik 1. Klinikum Grosshadem. Munich, Germany
Bcl-2 and neuronal
cell death.
Programmed Cell Death (PCD) or apoptosis occurs in most animal tissues at some stage during their development. Thus, approximately half of the neurons produced during embryogenesis die before adulthood. The number of neurons that die (or survive) seems to be controlled by neurotrophic factors supplied in limiting amounts by the targets cells that neurons innervate. Neurons that fail to get enough trophic factor die apparently by active suicide as, in some cases at least. their death can be prevented by RNA or protein syn( I ) Ltrrrcrr
t 1992)
304,
507
thesis inhibitors. The mechanisms by which trophic factors can interfere with PCD are unknown. Recently, we found that over expression of the Bcl-2 proto-oncogene in cultured sympathetic neurons prevents apoptosis normally induced by deprivation of the trophic factors nerve growth factor (NGF). Bcl-2 is a proto-oncogene that has been isolated from the chromosomal breakpoint of folicular B-cell lymphoma. The gene encodes a mitochondrial membrane protein that was shown primarily to block PCD in B and T lymphocytes. We do not know how Bcl-2 blocks PCD. We suggest that this protein may be a major mediator of the effects of neurotrophic factors on neuronal survival. Understanding the function of Bcl-2 could open new ways to treat diseases caused by too much cell death - Huntington’s disease and Parkinson’s disease for example - or too little cell death as may be the case in some cancers. Glaxo
Institute
JC Martinou (2) for Molecular Biology Geneva, Switzerland
Perixome biogenesis and Pas2 protein. In order to investigate the mechanisms of peroxisome biogenesis, we studied pas-mutants (Peroxisome nssembly) in the yeast Socchumnyes cerevisiae as a eukaryotic model system. These mutants are characterized by the absence of functional peroxisomes. In man, comparable peroxisomal deficiencies result in disorders such as Zellweger syndrome. neonatal adrenoleukodystrophy or infantile Refum disease. The Pas2-gene affected in the pas2-mutant was found to be a member of the family of ubiquitin-conjugating enzymes. These confer specificity of substrate recognition in the ubiquitination cascade, which leads to covalent ligation of ubiquitin to target proteins. The ubiquitination signal has been shown to be involved in a wide variety of cellular processes such as protein degradation, DNA repair, sporulation, and cell cycle control. Our results demonstrate the requirement for a ubiquitin-conjugating enzyme in peroxisome biogenesis. indicating a crucial role of the ubiquitination cascade in organelle formation.
D-4630 (2) Scirrrce (3) Nururc
(1992) (1992)
258. 302 359. 73
FF Wiebel(3) Ruhr-Universitlt. Bochum I, Germany