Proteomic experiments have produced a draft profile of the overall molecular composition of the mammalian neuronal synapse. It appears that synapses have over 1000 protein components and the mapping of their interactions, organization and functions will lead to a global view of the role of synapses in physiology and disease. A major functional subcomponent of the synaptic machinery is a multiprotein complex of glutamate receptors and adhesion proteins with associated adaptor and signalling enzymes totally 185 proteins known as the N-methyl-d-aspartate receptor complex/MAGUK associated signalling complex (NRC/MASC). Here, we review the proteomic studies and functions of NRC/MASC and specifically report on the role of its component genes in human diseases. Using a systematic literature search protocol, we identified reports of mutations or polymorphisms in 47 genes associated with 183 disorders, of which 54 were nervous system disorders. A similar number of genes are important in mouse synaptic plasticity and behaviour, where the NRC/MASC acts as a signalling complex with multiple functions provided by its individual protein components and their interactions. The individual gene mutations suggest not only an important role for the NRC/MASC in human diseases but that these diseases may be functionally connected by their common link to the NRC/MASC. The NRC/MASC is a rich source of genetic variation and provides a platform for understanding relationships of disease phenotype amenable to systematic studies such as the Genes to Cognition research consortium (www.genes2cognition.org) that links human and mouse genetics with proteomic studies.

Mechanisms of temperature adaptation in eukaryotes have been extensively studied during constant temperature acclimation, but relatively little is known about how organisms cope with life in fluctuating thermal environments. For free-living organisms, fluctuations may occur over time scales of hours to days or seasonally. Parasites can experience a change in their thermal habitat when they move between hosts during different life history stages. The malarial parasite, Plasmodium falciparum, is one such case. The first life stage occurs in the human host, which has a high body temperature, ranging from 37°C to 41°C during fever. The second two stages occur in the cooler mosquito host, which lives in habitats that commonly range from 20 to 30°C. In their Nature Brief Communication, Fang and McCutchan describe an investigation of the regulation of the transcription of a ribosomal RNA molecule in P. falciparum at different temperatures, which they hope will help us to understand how the parasite senses and reacts to it's changing environment.The team followed how one RNA component of the ribosome (a part of the cellular protein synthesis apparatus) was expressed when the parasite's cells were cultured at different temperatures. They already knew that this component of the ribosome was expressed as different isoforms, called A and S, during different stages of the parasite's life cycle. As these different life stages mark transitions from one temperature environment to another, they decided to monitor how expression of this component was affected by rearing parasite cells at different temperatures. They tracked the transcription of the RNA component using real-time PCR at 26, 31, 37 or 42°C to see how the expression profiles of A and S varied with temperature.At first they discovered that the A form of the RNA was expressed mostly during the first life stage, while the S form was expressed during the latter two life stages.Then they monitored the transcription of two separate isoforms of A and S to see if the parasite regulated their expression at different points in the parasite's life cycle. They found that both forms of A were expressed during the first life stage, but the parasite expressed S1 during the first developmental stage in the mosquito host, and switched to S2 when it progressed on to the second stage.When the team looked at the effect of temperature on the expression profiles of the four forms of the RNA subunit, they found that A expression levels were essentially the same at all four temperatures, but when they looked at the expression profiles of the S isoforms, they varied significantly at different temperatures. Neither form of S RNA was expressed at 42°C, the temperature found in a human with fever, but as they dropped the temperature, both forms began to be expressed at increasing levels. The S2 RNA was most dramatically affected; its expression level at 26°C was over 20 times the level at 37°C! The authors speculate that the cold-activation of S2 expression may be due to transcriptional control...

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