Background/ObjectiveParkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases.MethodsThis cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls.ResultsThe mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%.ConclusionDifferent parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes.

We characterized interactions between the human proteins Sec62 and Sec63 as well as the putative interaction of human Sec62 with ribosomes. The data demonstrate evolutionary conservation of Sec62/Sec63 interaction and indicate that in the course of evolution Sec62 of vertebrates has gained the additional function to interact with ribosomes.

Tryptophan metabolism occurs via the protohemoprotein enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), the latter action of which has a number of effects in the body including both antimicrobial defence and immune regulation. Whilst the antimicrobial action of IDO is largely due to depletion of the essential amino acid tryptophan, the immune regulatory function of IDO is still unclear and controversial. The list of pathogens that are "sensitive" to IDO-mediated tryptophan degradation covers intra-cellular parasites such as toxoplasma and possibly plasmodia, viruses (herpes viruses) to intra-cellular bacteria (chlamydia and rickettsia) and extra-cellular bacteria such as streptococci, enterococci and staphylococci. Immune regulation may be a consequence of tryptophan depletion, the accumulation of immune-active or toxic metabolites or due to other signalling events. This review covers the latest data and controversy pertaining to the antimicrobial and immune regulatory effects of tryptophan metabolism.

ERj1p is a membrane protein of the endoplasmic reticulum (ER) that can recruit the ER lumenal chaperone BiP to translating ribosomes. ERj1p can also modulate protein synthesis at initiation and is predicted to be a membrane-tethered transcription factor. Here we attribute the various functions of ERj1p to distinct regions within its cytosolic domain. A highly positively charged nonapeptide within this domain is necessary and sufficient for binding to ribosomes. Binding of ERj1p to ribosomes involves the 28S ribosomal RNA and occurs at the tunnel exit. Additionally, ERj1p has a dual regulatory role in gene expression: ERj1p inhibits translation in the absence of BiP, and another charged oligopeptide within the cytosolic domain of ERj1p mediates binding of the nuclear import factor importin beta and import into the nucleus, thereby paving the way for subsequent action on genomic DNA.

In mammals, the regulation of local tryptophan concentrations by the IFN-c-i inducible enzyme IDO is a prominent antimicrobial and immunoregulatory effector mechanism. Here, we show for the first time that another tryptophan-degrading enzyme, the liverspecific tryptophan 2,3-dioxygenase (TDO), is also capable of mediating antimicrobial and immunoregulatory effects. Using a tetracycline inducible eukaryotic system, we were able to express recombinant TDO protein, which exhibits functional properties of native TDO. We found that HeLa cells expressing recombinant TDO were capable of inhibiting the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) and viruses (herpes simplex virus). These TDO-mediated antimicrobial effects could be blocked by the addition of tryptophan. In addition, we observed that, similar to IDO-positive cells, TDOpositive cells were capable of inhibiting anti CD3-driven T-cell proliferation and IFN-c production. Furthermore, TDO-positive cells also restricted alloantigen-induced T-cell activation. Here, we describe for the first time that TDO mediates antimicrobial and immunoregulatory effects and suggest that TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation.Key words: Kynurenine . T cells . Tolerance . Tryptophan . Tryptophan 2,3-dioxygenase Introduction L-tryptophan (L-trp) is an essential amino acid that is not only required for the synthesis of proteins, but also for the biosynthesis of neurotransmitters such as serotonin and melatonin. Nevertheless, most of the dietary L-trp is catabolised via the kynurenine pathway to kynurenines and these are eliminated in the urine (hence their names). A small amount of the dietary tryptophan is used to produce the physiological relevant NAD [1,2].In mammals, the first and rate-limiting step of the kynurenine pathway, namely the oxidation of tryptophan to N-formyl kynurenine, is catalysed by the hepatic tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and the extra-hepatic IDO (EC 1.13.11.52). Recently, a third tryptophan-degrading enzyme, IDO2, was described, however, the in vivo function of this enzyme remains speculative [3,4].The function of IDO has been most intensively analysed and shown to be involved in several essential processes. Being an immunoregulated enzyme with antimicrobial and immunoregulatory function, IDO regulates T-cell responses and induces maternal tolerance towards the allogeneic foetus [5]. Interestingly, IDO also seems to play a role in cancer progression as the magnitude of its expression, for example, correlates with the overall survival of serous-type ovarian cancer patients, specifying IDO as a marker for a poor prognosis [6].IDO mediates its activity locally, in inflamed tissue or lymph nodes. In contrast, TDO activity is mainly expressed in the liver and is not regulated by the immune system but does have à These authors contributed equally to this work. systemic effects by controlling the tryptophan levels in ...

Migrating cells are guided in complex environments mainly by chemotaxis or structural cues presented by the surrounding tissue. During transmission of malaria, parasite motility in the skin is important for Plasmodium sporozoites to reach the blood circulation. Here we show that sporozoite migration varies in different skin environments the parasite encounters at the arbitrary sites of the mosquito bite. In order to systematically examine how sporozoite migration depends on the structure of the environment, we studied it in micro-fabricated obstacle arrays. The trajectories observed in vivo and in vitro closely resemble each other suggesting that structural constraints can be sufficient to guide Plasmodium sporozoites in complex environments. Sporozoite speed in different environments is optimized for migration and correlates with persistence length and dispersal. However, this correlation breaks down in mutant sporozoites that show adhesion impairment due to the lack of TRAP-like protein (TLP) on their surfaces. This may explain their delay in infecting the host. The flexibility of sporozoite adaption to different environments and a favorable speed for optimal dispersal ensures efficient host switching during malaria transmission.

Recently, the homolog of yeast protein Sec63p was identified in dog pancreas microsomes. This pancreatic DnaJ-like protein was shown to be an abundant protein, interacting with both the Sec61p complex and lumenal DnaK-like proteins, such as BiP. The pancreatic endoplasmic reticulum contains a second DnaJ-like membrane protein, which had been termed Mtj1p in mouse. Mtj1p is present in pancreatic microsomes at a lower concentration than Sec63p but has a higher affinity for BiP. In addition to a lumenal J-domain, Mtj1p contains a single transmembrane domain and a cytosolic domain which is in close contact with translating ribosomes and appears to have the ability to modulate translation. The interaction with ribosomes involves a highly charged region within the cytosolic domain of Mtj1p. We propose that Mtj1p represents a novel type of co-chaperone, mediating transmembrane recruitment of DnaK-like chaperones to ribosomes and, possibly, transmembrane signaling between ribosomes and DnaK-like chaperones of the endoplasmic reticulum.

Amyotrophic lateral sclerosis (ALS) is characterized by neuro-ophthalmological abnormalities beyond disturbed oculomotor control such as decreased visual acuity and disturbed visual evoked potentials. Here we report retinal alterations in a cohort of 24 patients with clinically definite (n = 20) or probable (n = 4) ALS as compared to matched controls. High-resolution spectral domain optical coherence tomography with retinal segmentation revealed a subtle reduction in the macular thickness and the retinal nerve fiber layer (RNFL) as well as a marked thinning of the inner nuclear layer (INL). Our data indicate an unprecedented retinal damage pattern and suggest neurodegeneration beyond the motor system in this disease.