Stemming brain cancer

The BMP4 receptor (red) on stem cell–like cancer cells. Credit: Nature

Research on stem cells uncovers a potential treatment for glioblastoma, one of the deadliest of cancers (Nature 444, 761–765).

Glioblastomas are thought to get much of their kick from a population of cancer cells with stem cell–like properties. Piccirillo et al. found that these cells expressed bone morphogenic proteins (BMPs) and their receptors, proteins that are involved in the differentiation of normal adult brain cells. They found that administering BMP4 could block tumor growth and prolong life in mice transplanted with human glioblastoma cells.

Other recent findings have identified a population of cells with stem cell–like properties in colon cancer (Nature, doi:10.1038/nature05384, doi:10.1038/nature05372). Whether BMP4 might counteract this and other cancers remains to be tested.—CS

Problem proteins in PD

Mutations associated with inherited forms of Parkinson disease have come to light recently—but it is still unclear how they lead to the death of dopaminergic neurons in the brain, a key event in this disease. Studies on two genes, α-synuclein and LRRK2 (leucine-rich repeat kinase-2), address how such neuronal dysfunction may occur.

David Sulzer and colleagues found that cell lines overexpressing mutant α-synuclein had impaired dopamine release, a deficit linked to dysfunctional exocytosis of dopamine-containing vesicles (J. Neurosci. 26, 11915–11922). Whether mutant α-synuclein interferes with dopamine release in neurons, and whether these problems contribute to dopaminergic neuron death, remains unclear.

A study in cells and rats (Neuron 52, 587–593) suggests that mutant LRRK2 reduces the formation of neurites, branch-like projections from a neuron's cell body that give rise to axons and dendrites. Asa Abeliovich and colleagues found that the kinase encoded by mutant LRRK2 exhibited increased activity and seemed to prompt neuronal death and inhibit neurite outgrowth; conversely, knocking down LRRK2 expression increased neurite length. Additionally, neurons that expressed mutant LRRK2 contained tau aggregates, which are also present in the brains of some individuals with Parkinson disease caused by LRRK2 mutations. The effect of mutant LRRK2 on tau may shed light on other diseases that also exhibit tau aggregation, such as Alzheimer disease.—EC

Uncovering autism

Two studies have uncovered genes associated with autism.

Christelle Durand et al. found mutations in SHANK3 in three families afflicted with the disease (Nat. Genet. 39, 25–27; 2006). Shank-3 binds multiple proteins that regulate functions at the neuronal synapse, including neuroligins. Since genes encoding neuroligins have been previously associated with autism, the findings suggest that these proteins and associated factors could be scrutinized in the search for a biological basis of autism.

Daniel Campbell et al. (PNAS 103, 16834–16839) report that mutations in the gene encoding the MET receptor tyrosine kinase raise the risk for autism. How MET may operate in the disease is unclear, although it is involved in neural development.—CS

Partners in drug crime

Behavioral responses to cocaine depend on the physical interaction between dopamine receptors and glutamate receptors, according to a study in Neuron (52, 897–909).

Interactions between dopamine and glutamate modulate the action of psychostimulant drugs, but the molecular mechanisms have been hard to pin down. Xian-Yu Liu et al. found that cocaine administration to rats triggered the formation of a complex between dopamine D2 receptors (D2R) and NR2B glutamate receptors in the striatum—a region of the brain highly susceptible to drugs of abuse. This interaction reduced NR2B phosphorylation and inhibited receptor function in vitro. Crucially, disrupting the D2R-NR2B interaction in vivo prevented the stereotyped behaviors, such as sniffing and biting, and the increase in locomotor activity seen after exposure to cocaine.

Future studies should test whether this interaction is relevant to the addictive properties of cocaine. —JCL

HIV-malaria linkage

Episodes of malaria can cause levels of HIV virus to spike in the blood; conversely, HIV-infected patients have increased susceptibility to malaria. Laith Abu-Raddad et al. explore the public health implications of this dynamic (Science 314, 1603–1606).

The researchers created a mathematical model and applied it to a region in Kenya with an adult population of approximately 200,000. The researchers estimate that since 1980, the interaction between the two diseases may have been responsible for 8,500 more HIV infections than if malaria were not present, and 980,000 excess malaria episodes. Thus efforts to quell one disease could have a big impact on the other.—CS

Handle on hormones

Mammary glands branch out in Brca1-deficient mouse. Credit: Science

BRCA1 is widely expressed, yet when mutations arise in this gene, it's the breast and ovarian tissue that are most susceptible to cancer. A report in Science (314, 1467–1470) examines this conundrum and suggests a new strategy against BRCA1-deficient tumors—administration of the progesterone receptor antagonist RU486 (mifepristone), perhaps best known as an abortion drug.

Previous research had found that BRCA1 interacts with both the estrogen and progesterone receptors, and Aleksandra Jovanovic Poole et al. considered whether this might underlie the specific effects of BRCA1 mutations in hormone-responsive tissues. The investigators analyzed a mouse cancer model lacking Brca1 and the tumor suppressor p53. The mammary epithelial cells in these mice showed increased proliferation, an effect that could be amplified by estrogen or progesterone. What's more, treating the mice with RU486 prevented tumor development.

The absence of Brca1 resulted in stabilization of the progesterone receptor, which may account for the cells' enhanced proliferative response to progesterone. If these results hold up in human breast cancer cells, RU486 may be useful as a prophylactic treatment in carriers of BRCA1 mutations. —AF

Written by Eva Chmielnicki, Alison Farrell, Juan Carlos López and Charlotte Schubert.