Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.
Schizophrenia and bipolar disorder (manic-depressive psychosis) are two major psychotic illnesses. They affect about 2 percent of the population.
Previous research has suggested abnormalities in expression of lipid and myelin-related genes in schizophrenia. Oligodendrocytes produce the myelin sheaths, which insulate nerve cells. Myelin is 80 percent lipid and 20 percent protein. It enables the efficient conduction of electrical impulses down the neuronal axon.
Authors of a study in The Lancet, dated Sept. 6, 2003, offer strong evidence that schizophrenia and bipolar disorder have a similar genetic cause. This supposedly arises from reduced expression of genes responsible for myelin development of the central nervous system. Their paper carries the title "Oligodendrocyte dysfunction in schizophrenia and bipolar disorder." Its senior author is neurobiologist Sabine Bahn at the Brabraham Institute, University of Cambridge in the UK.
The journal article's investigators used microarray/postmortem assessment to compare gene expression in the preserved brains of 15 people who had schizophrenia, 15 with bipolar disorder, and a control group from 15 subjects who had neither illness. In the first two groups, they encountered a clear reduction in myelin-related genes, with a high degree of overlap.
An accompanying commentary by research psychiatrist Kenneth Davis at Mount Sinai School of Medicine in New York is titled "Global-expression-profiling studies and oligodendrocyte dysfunction in schizophrenia and bipolar disorder." It stated, "The observation that at least some myelin-related gene-expression deficits are common between individuals with schizophrenia and bipolar disorder is intriguing because schizophrenia and bipolar disorder have different symptom profiles and require treatment based on quite different neurotransmitter systems."
The design of The Lancet study, Davis' editorial continued, "precludes ascertaining whether common myelin-related neurobiological features identified between these diseases are due to a sharing of psychotic symptoms. Would similar overlaps in gene-expression profiles be seen in individuals that have non-psychotic bipolar disorder and those with schizophrenia? The answer to this question will have to come from studies of well-characterized postmortem material from patients diagnosed before death.
"The rough coincidence in age," Davis's commentary continued, "for the myelination of the prefrontal cortex, the onset of schizophrenic symptoms and oligodendrocyte-related genes differentiate between mature and progenitor cells. They found that genes exclusively expressed in oligodendrocyte progenitors are not abnormally expressed in schizophrenia. Although these findings suggest that abnormalities in cell lineage and progenitor pathology are unlikely to be major components of schizophrenia and bipolar disorder, these results do not exclude dysfunction of other oligodendrocyte-related developmental processes."
A Paradox: Protein Levels Of Aging Organelles Go Up, Not Down; Needed For Repair Of ROS
Impaired transport of DNA repair proteins into the mitochondria of older cells may contribute to the aging process. Mitochondria - organelles that serve as cellular power plants - contain their own genetic material, which accumulates damage with advancing age.
The Proceedings of the National Academy of Sciences (PNAS) reports this process in its online edition dated Sept. 2, 2003. The paper's title: "Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases." Its co-authors are at the University of Texas Medical Branch in Galveston.
Age-related increases in DNA damage suggest that the activity of mitochondrial DNA repair proteins, such as OGG1, might decrease with age. Surprisingly, however, previous research showed that OGG1 levels actually increased with age in the mitochondria of rodent liver cells. To address this paradox, the co-authors investigated the behavior of the repair protein as it crossed the membranes of aged mitochondria. They confirmed elevated levels of the repair protein in the aged liver mitochondria of mice and in cell culture of aged human fibroblasts.
However, a significant fraction of the repair protein was stuck in the mitochondrial membrane where it was unable to reach the damaged DNA inside. These results suggest that the mitochondrial import machinery may be impaired due to aging. They propose that the deficiency contributed to the aging syndrome by hindering DNA repair - and possibly other crucial cellular functions.
These results formed the basis of the mitochondrial theory of aging, which postulates that the accumulation of DNA damage and mutations in the mitochondrial genomes causes mitochondrial dysfunction, leading to chronic production of reactive oxygen species (ROS), and contributing to the development of the age-associated decline in tissue functions. The major source of ROS in the cell is the mitochondria. Its genomes are more susceptible to oxidative damage than the nuclear genome, presumably because of the physical proximity of the source of ROS.
More Than 300 Genes Of Unknown Function Await Dystrophic Clarification By Subtractive Proteomics
Just say the word "dystrophy" and the trigger term pops up: "Duchenne muscular." It's the most common childhood muscular dystrophy, which sets in usually before age 6. The disorder is marked by symmetric progressive weakness and wasting of skeletal muscles. The disease implicates the heart, sometimes mild mental retardation, progressive course and early death, usually in adolescence. It affects males and is transmitted by females.
Science dated Sept. 5, 2003, carries the article's title: "Nuclear membrane proteins with potential disease links found by subtractive proteomics." Its co-authors are a team of scientists at the Scripps Research Institute in La Jolla, Calif.
They have identified more than 50 previously unknown proteins, and associates several of them with rare human muscle and nerve degeneration diseases. They used the technique of subtractive proteomics to identify 62 new proteins in the inner nuclear membrane of the human cell. They demonstrated that 23 of these proteins very probably are linked to 14 rare muscle-wasting diseases, such as congenital muscular dystrophy, Limb-Girdle muscular dystrophy and spinal muscular dystrophy. They added several forms of the neurodegenerative Charcot-Marie-Tooth disease.