Joseph Grimsby

Bio: Joseph Grimsby is an academic researcher from University of Southern California. The author has contributed to research in topics: Monoamine oxidase A & Monoamine oxidase. The author has an hindex of 11, co-authored 14 publications receiving 2596 citations.

Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

Abstract: Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.

Human monoamine oxidase A and B genes exhibit identical exon-intron organization.

Abstract: Monoamine oxidases A and B [MAOA and MAOB; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] play important roles in the metabolism of neuroactive, vasoactive amines and the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Human MAOA and MAOB genes isolated from X chromosome-specific libraries span at least 60 kilobases, consist of 15 exons, and exhibit identical exon-intron organization. Exon 12 codes for the covalent FAD-binding-site and is the most conserved exon; the MAOA and MAOB exon 12 products share 93.9% peptide identity. These results suggest that MAOA and MAOB are derived from duplication of a common ancestral gene and provide insight on the structural/functional relationship of the enzyme products.

Increased stress response and β–phenylethylamine in MAOB –deficient mice

Abstract: MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines1–5. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and nore-pinephrine (NE), whereas MAOB preferentially oxidizes β-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control6,7. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease8,9, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-ll alcoholism and in cigarette smokers10,11. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect12,13. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

Initial sequencing and analysis of the human genome.

Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Mitochondrial formation of reactive oxygen species.

Abstract: The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2−•). Even though O2−• is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.

Role of Genotype in the Cycle of Violence in Maltreated Children

Abstract: We studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children's sensitivity to environmental insults.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

Abstract: Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.