DISCOVERIES IN NEUROSCIENCE September 2009

A STEP toward neuroprotection

Excessive stimulation of NMDA receptors, important in the pathogenesis of injury in the setting of stroke, epilepsy and global ischemia, can have opposing effects on neuronal survival or cell death. The findings presented in this study shed light on this apparent paradox. The investigators show that differential regulation of STEP₆₁, striatal enriched protein tyrosine phosphatase, can determine whether a cell lives or dies. Stimulation of synaptic NMDARs activates the Ras-extracellular signal regulated kinase (ERK) – cAMP response element –binding protein (CREB) pathway and translation of prosurvival proteins while stimulation of extrasynaptic NMDARs activates proapoptotic proteins through phosphorylation of p38. In an elegant series of experiments, the investigators show that STEP₆₁ regulates the activation state of both p38 and ERK. Synaptic stimulation selectively induces ubiquitination and degradation of STEP₆₁ and phosphorylation of ERK while extrasynaptic stimulation causes calpain dependent cleavage of STEP₆₁ with phosphorylation of p38. Using a TAT-STEP peptide to prevent the cleavage of STEP, they were able to show neuroprotection in cortical cultures through the reduction of phosphorylation of p38 and attenuation of Bax translocation. In STEP knockout mice, they observed an increase p38 signaling and susceptibility to oxygen glucose deprivation in tissue slices. These findings implicate STEP as a key player and valid target for the neuroprotective therapies (J Neurosc 2009, 29:9330-9343).

Interleukin 21 drives alemtuzumab secondary autoimmunity

Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against CD52, a small GPI-anchored receptor expressed in leukocytes. A single pulse of treatment leads to a rapid, profound and prolonged lymphopenia. An approved treatment for B cell chronic lymphocytic leukemia, this reagent has been used to control GVHD, to improve engraftment, and more recently to efficiently treat early multiple sclerosis. Surprisingly, phase II clinical trials in MS revealed a high incidence of secondary autoimmunity, usually targeting the thyroid gland. Based on early observations in the autoimmune-prone NOD mouse strain, Jones and colleagues hypothesized that secondary autoimmunity following alemtuzumab treatment develops primarily in individuals with greater T cell cycling and apoptosis driven by the overproduction of interleukin-21. IL-21 is produced mostly by activated CD4+ T cells and regulates the function of effector T helper cells and production of inflammatory mediators by non-immune cells. The authors show that a two-fold IL-21 serum concentration at baseline was characteristic of the individuals who will develop secondary autoimmunity. Interestingly, a polymorphism in the IL-21 gene appears to be associated with increased production of the cytokine. The authors conclude that a genetically determined capacity for high production of IL-21 renders individuals susceptible to secondary autoimmunity by accelerating cycles of T cell expansion and apoptosis in response to the drug-induced lymphocyte depletion. Although the mechanisms underpinning this phenomena are not yet fully elucidated, IL-21 as a genetic and/or serological biomarker my serve to counsel those considering treatment with this drug (J Clin Invest 2009, 119:2052-2061).

Separating headache from aura

Cortical spreading depression (CSD) is a phenomenon characterized by a slowly spreading depolarization of cortical cells and is postulated to cause aura associated with migraine. Recently drugs that block gap junctions have been developed to inhibit CSD. In this paper the authors tested the effect of one such drug, tonabersat in patients with migraine. They examined 39 patients in a double blind crossover study and measured attacks of aura with or without headache and migraine headache days with or without aura as primary outcomes. The results showed that tonabersat reduced the number of aura attacks and attacks of aura followed by headache but not the number of migraine headache days. These results suggest that migraine with aura and migraine without aura involve different pathophysiological mechanisms. The study also suggests that drugs targeting gap junctions may be effective in treating migraine with aura (Lancet Neurol 2009 8:718-723).

Adding yet more to neural complexity – Retrotransposons!

Retrotransposons are sequences of DNA found in eukaryotes that have the capacity to replicate and insert themselves throughout the genome. As such, they can disrupt coding sequences and alter gene expression, and hence the phenotype of dividing cells. In this remarkable study, Coufal and colleagues show that that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered long interspersed element 1 (L1) retrotransposons in vitro. Furthermore, using a new quantitative method for detecting retrotransposon copy numbers in vivo, they detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism (Nature. 2009; August 5 Epub. PMID:19657334).

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