Even though my background is in neuroscience, I rarely write about this topic. But wo papers on amyotrophic lateral sclerosis (ALS) from the latest issue of the Journal of Neuroscience struck me as interesting to talk about.

In the first one, Fiona Laird and her colleagues generated transgenic mice that express wild-type and mutant forms of the human protein dynactin p150-Glued. As mutant forms of this molecule had been linked to ALS, they decided to explore the mechanism whereby dynactin p150-Glued contributes to the pathology. They found that expression of dynactin p150-Glued carrying a mutation that had been linked to the disease in patients led to motor neuron disease in transgenic mice, something that was not seen in mice overexpressing the wild-type form of the human protein.

The paper is very nice in that it provides a very detailed account of the neuropathology the authors see in the mouse, including some intriguing evidence of autophagic cell death. The picture below, which comes from the paper, is a silver-stained section of the spinal cord from a mutant mouse, showing dark, presumably dying, motor neurons (arrowheads) that are not seen in control mice. Unfortunately, the authors didn’t get to explore the hardcore molecular mechanisms that account for the motor neuron death. But they now have a useful system to ask more mechanistic questions to understand the role of dynactin p150-Glued in cell death and investigate its actual relationship to human ALS.

The second study deals with a question that has occupied the field for some time. We know that mutations in superoxide dismutase (SOD) are linked to familial forms of ALS, but where does SOD need to be expressed to cause disease: in neurons, in glia, in muscle? Dick Jaarsma and his colleagues tried to get at this question by generating transgenic mice that expressed mutant SOD only in neurons. The figure below, from the original paper, shows spinal cord sections from mice that expressed the mutant protein only in neurons (top left and bottom right) or ubiquitously (top middle).

This is not the first time that neuron-specific expression of SOD has been tried, but it is perhaps the first time in which it is found to effectively kill the motor neurons. In other words, these findings fly in the face of other studies reporting no motor neuron death in mice with neuron-specific expression of mutant SOD and of papers specifically identifying a contribution of extraneuronal SOD to ALS. Not unexpectedly, there is at present no definitive way to reconcile these disparate observations, other than invoking technical differences in the studies or stating that the cell-autonomous effect reported by Jaarsma et al. does not negate an additional contribution from glial SOD. What we can say for sure is that we don’t yet understand the neuron/glia/muscle interplay in ALS, and that it will be quite hard to establish if the contributions of mutant SOD from each of these sources in transgenic mice are indeed relevant to the human condition.

As I approach the age at which the word ‘prostate’ starts sounding like a funereal drum, I become more interested in studies such as those published this week in the NEJM and about three weeks ago in Nature Genetics.

The NEJM paper, by Lilly Zheng and colleagues, shows that single-nucleotide polymorphisms (SNPs) in five chromosomal regions, each of which had previously and independently been associated with prostate cancer, have a cumulative association with the disease when considered in combination. The authors estimate that the five SNPs and a family history of prostate cancer account for as many as 46% of the cases in the Swedish population they studied.

The three Nature Genetics papers, by Julius Gudmundsson et al., Gilles Thomas et al. and Rosalind Eeles et al., all of which are nicely summarized in the journal’s March editorial, disclose multiple new susceptibility loci associated with prostate cancer that, together with other loci identified in 2006 and 2007, give us plenty of new avenues to explore in order to understand the disease.

The most immediate implication of findings of this sort is often diagnostic — if you identify gene variants that are linked to a disease, you can ask questions about how good these variants are at predicting onset and/or progression of the pathology. Validating the diagnostic value of these genomic data often requires blinded samples analyzed in a prospective (preferably longitudinal) fashion.

The findings could also help us understand the biology of the disease, although this almost always takes more time and is not always pursued, as it is very challenging: you need to identify with precision the protein whose gene harbors the relevant SNP, then establish how the SNP affects protein function, and finally look at how this altered function modifies the physiology of the cell as it becomes tumorigenic in an in vivo setting.

This is what we at Nature Medicine look for when we evaluate submissions that report new associations of SNPs or mutations with disease, which is why we don’t tend to publish too many of these kind of studies. That said, these ruminations do not take anything from the value of these four studies, which shine some more light on the black box that prostate cancer has turned out to be.

In addition to the Insight on Cardiovascular Disease, edited by Nature Medicine‘s own Michael Basson, a couple of papers caught my attention from this past Thursday’s issue of Nature.

First, the analysis of multiple sclerosis (MS) lesions by laser-capture microdissection and proteomics, which led May Han and colleagues to identify two potential therapeutic targets for the disease — tissue factor and protein C inhibitor — both of which participate during coagulation. Indeed, the authors went on to show that blocking the action of thrombin (which signals downstream of tissue factor) or administering activated protein C (to counter the increased levels of its inhibitor) ameliorated pathology in an animal model of MS. The image below, from the Nature paper, shows astrogliosis in a chronic MS plaque, revealed by and anti-GFAP antibody.

Second, the discovery by Xiaoyong Yang and colleagues of a link between O-GlcNac transferase and insulin resistance. We already knew that glucose flux through the hexosamine biosynthetic pathway leads O-GlcNac transferase to attach the sugar O-linked beta-N-acetylglucosamine (O-GlcNac) to proteins, thereby acting as a nutrient sensor. The new study shows that O-GlcNac transferase has a binding site for phosphatidylinositol 3,4,5-trisphosphate (PIP3), a key mediator of insulin signaling. Upon binding, PIP3 recruits O-GlcNac transferase to the plasma membrane, where it sticks O-GlcNac to proteins of the insulin signaling pathway, reducing their responsiveness to insulin (see the figure below, which I borrowed from the paper; O-GlcNac transferase is labeled as OGT). In vivo, liver overexpression of O-GlcNac transferase causes insulin resistance, pointing to the likely functional relevance of this mechanism.

Two sets of papers caught my attention over the past couple of days. Apologies if they are old hat for those of you who work in these fields. It’s hard to keep up with all the ToC alerts I get.

The first is a doublet from Nature on the mechanism whereby certain tumors acquire resistence to chemotherapy. The studies, by Wataru Sakai and colleagues and by Stacey Edwards and colleagues focused on tumors that carry mutations in BRCA2 and are therefore sensitive to platinum compounds like cisplatin. In some cases, these tumors develop resistance to cisplatin, and what both studies show is that the development of resistance depends on the appearance of new mutations in BRCA2, which restore the open reading frame of the protein. Although this is perhaps not incredibly surprising, particularly because similar secondary mutations had been observed in cases of resistance to imatinib in leukemia, this finding has obvious clinical implications for people who become unresponsive to cisplatin.

The other paper, by Marielle Gold and her colleagues in PLoS Pathogens, reports on the existence of a novel population of human T cells that innately recognize Mycobacterium tuberculosis (Mtb). These cells, which the authors isolated from newborns who were very unlikely to have ever been exposed to the bacterium, exist at relatively high frequencies and respond to Mtb-infected cells by producing IFN-γ. The authors assert that this is the first demonstration of a human innate pathogen-specific T cell and refer to preliminary experiments showing that other thymocytes can also respond to other pathogens including Staphylococcus aureus and Escherichia coli. How this innate recognition comes about in the fisst place strikes me as a pretty interesting question for follow-up studies.