In This Issue
BIOPHYSICS
Natural osmoprotectant and neurodegenerative disease
Protein aggregation is a hallmark of several late-onset neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s diseases. Zoya Ignatova and Lila Gierasch report that proline, a naturally occurring osmolyte (a small organic molecule that allows cells to cope with osmotic stress), can stop protein aggregation in vitro and in vivo, including the aggregation of a protein containing the pathogenic exon of the huntingtin gene. The authors found that proline, when present along with salt to activate proline import, impeded the formation of insoluble protein aggregates in an Escherichia coli model. In vitro findings recapitulated these in vivo effects. Increased proline concentration also altered the aggregation ability of the protein fused with huntingtin exon 1. Although it did not entirely abolish the aggregation of the fusion protein, the osmolyte’s presence led to the accumulation of detergent-soluble aggregates. Typical Huntington’s disease aggregates are fibrillar and detergent-insoluble. The results may help in the application of osmolytes to biomedical therapeutics, as well as in biotechnological processes such as large-scale bacterial protein expression. — F.A.
Effect of the osmolyte proline on protein aggregation.
“Inhibition of protein aggregation in vitro and in vivo by a natural osmoprotectant” by Zoya Ignatova and Lila M. Gierasch (see pages 13357–13361)
CELL BIOLOGY
“Death-homing” receptor aids apoptosis
When apoptosis (programmed cell death) is initiated in the roundworm Caenorhabditis elegans, the proapoptotic protein CED-4 transfers from the mitochondrial membrane to the nuclear envelope. Yonatan Tzur et al. have identified the inner nuclear membrane protein, matefin/SUN-1, that acts as the receptor that binds to and localizes CED-4 at the nuclear envelope, linking cytoplasmic and nuclear apoptotic events. The authors demonstrated that down-regulation of the matefin/SUN-1 receptor in C. elegans embryos by RNA interference prevented CED-4 translocation after the induction of apoptosis, although the protein disassociated from the mitochondria. Embryos that escaped early embryonic lethality had a greatly reduced number of apoptotic cell corpses compared with wild-type embryos. The down-regulation of other nuclear envelope proteins (such as lamin and LEM-domain proteins) did not affect CED-4 translocation. Tzur et al. say that SUN-domain proteins could have similar roles in mammalian cells, acting as receptors for “death-homing” complexes in specific nuclei destined for apoptosis. — F.A.
C. elegans embryo with reduced matefin/SUN-1.
“Matefin/SUN-1 is a nuclear envelope receptor for CED-4 during Caenorhabditis elegans apoptosis” by Yonatan B. Tzur, Ayelet Margalit, Naomi Melamed-Book, and Yosef Gruenbaum(see pages 13397–13402)
MEDICAL SCIENCES
Polymorphism associated with preterm delivery in African-Americans
African-American women have a significantly increased risk of delivering prematurely compared with other races, and recent research has identified a functional single-nucleotide polymorphism (SNP), called the minor “T” allele, in the promoter region of the SERPINH1 gene, which is highly enriched in people of African ancestry. This gene encodes for a heat shock protein that stabilizes collagen, which is deficient in premature preterm rupture of membranes (PPROM), the leading identifiable cause of preterm birth. Hongyan Wang et al. report that the SERPINH1 polymorphism greatly increases the risk of PPROM in African-American women, correlating an ancestry informative marker with a pregnancy complication. The minor “T” allele displayed reduced promoter activity in amnion cells, which are responsible for producing collagen, and generated decreased SERPINH1 expression. In two separate, case-controlled studies, the polymorphism occurred almost three times more frequently in neonates born from pregnancies complicated by PPROM in African-American women. The “T” allele had increased promoter activity in uterine muscle cells, raising the possibility that it contributes to the formation of collagen-rich uterine fibroid tumors, which are also more common in women of African descent. These findings could aid development of therapeutics for improving reproductive health in African-American women, the authors say. — F.A.
Dye-stained fetal membrane.
“A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans” by Hongyan Wang, Samuel Parry, George Macones, Mary D. Sammel, Helena Kuivaniemi, Gerard Tromp, George Argyropoulos, Indrani Halder, Mark D. Shriver, Roberto Romero, and Jerome F. Strauss III (see pages 13463–13467)
MEDICAL SCIENCES
Game theory and cooperation between cancer cells
The evolution of cooperation between individuals and groups has a theoretical basis in game theory. An analysis of tumor cells using game theory reveals unique ways that cancer can evolve. Robert Axelrod et al. considered individual tumor cells as “game players” and studied how cooperation could evolve between different clonal populations. The authors showed that precancerous cells can cooperate to avoid host defenses, giving them the opportunity to become true cancer cells. Such cooperation could occur if two cells each secreted a different growth factor required by both and where one cell cannot synthesize the factor made by the other. Also, the first cell to promote new blood vessel growth to feed a given tumor could provide cooperative benefit to all other nearby precancerous cells. Axelrod et al. also showed how the cooperation of tumor cells and their recruitment of otherwise normal supporting cells to enable metastasis can be more easily understood in terms of game theory. The game theory analysis provided unique ways of looking at cooperation in cancer, including examining shared resources and abilities and the timing and expected order of mutations. Investigating these questions could lead to improved understanding of how certain cancer treatments succeed or fail. — P.D.
Intratumor cooperation.
“Evolution of cooperation among tumor cells” by Robert Axelrod, David E. Axelrod, and Kenneth J. Pienta (see pages 13474–13479)
NEUROSCIENCE
Neuroprotection by antioxidants in Parkinson’s fly model
Parkinson’s disease, which affects 1–2% of people over 65 years of age, is a neurodegenerative illness that results in the death of dopamine-producing neurons. Although most Parkinson’s disease cases are not inherited, some are linked to specific, inherited mutations. Using a Drosophila fly model, Danling Wang et al. report that antioxidants can compensate for a defective gene and protect neurons from the cell death associated with Parkinson’s disease. The authors investigated the genetic roots of Parkinson’s disease-related neuronal damage in Drosophila by examining the role of the PINK1 gene. Changes in the PINK1 gene have been implicated in development of Parkinson’s disease in both inherited and sporadic cases. Wang et al. inactivated the PINK1 gene in Drosophila by silencing the gene’s transcript in a process known as RNA inactivation. Flies with a silenced gene showed reduced numbers of dopamine-producing neurons in the brain, and adding back the human form of the gene prevented the neuronal death. Treating the flies with antioxidants, such as vitamin E, also rescued the neurons from cell death. The authors suggest that PINK1 protects neurons from oxidative stress and that its absence leads to the cell death associated with development of Parkinson’s disease. — T.D.
PINK1 gene inactivation results in loss of retinal neurons.
“Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila” by Danling Wang, Li Qian, Hui Xiong, Jiandong Liu, Wendi S. Neckameyer, Sean Oldham, Kun Xia, Jianzhi Wang, Rolf Bodmer, and Zhuohua Zhang (see pages 13520–13525)
