Band 1, Heft 4

Reduced levels of the survival of motor neurons protein (SMN), cause the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The majority of therapeutic approaches to date have been focused on finding ways to increase expression of functional SMN protein, though stabilization of SMN protein may also be an important consideration. SMN interacts, directly or indirectly, stably or transiently, with a large number of other proteins, some of which contribute to SMN stability and may therefore be potential targets for SMA therapy. We recently characterized the nuclear SMN interactome using LC-MALDI-TOF/TOF analysis of anti-SMN pull-downs and identified myb-binding protein-1a (Mybbp1a) as a novel partner. In light of interest in cytoplasm-specific roles of the SMN complex, we have applied the same approach to characterise the cytoplasmic SMN interactome. We now show that SMN complexes from HeLa cytoplasmic extracts differ significantly from those found in nuclear extracts, with gemin5, importinbeta and annexin A2 easily detected only in the cytoplasmic extracts, whereas interaction of SMN with Mybbp1a appears to occur only in the nucleus. SMN is ubiquitinylated and we also found proteins of the ubiquitin-proteasome system associated with SMN in the cytoplasm.

Spinal cord injury (SCI) can be a lifelong, devastating condition for both the patient and the caregiver, with a daunting incidence rate. Still, there are only limited available therapies and the effectiveness of precise regeneration within the central nervous system is minimal throughout postnatal life. Recently, improved regeneration after SCI was seen by manipulating a pathway in sensorimotor neocortices that is involved in phosphorylation of an RNA binding protein (RBP) required for mRNA translation, the Eukaryotic translation initiation factor 4E (eIF4E). Our data identifies rapid molecular alterations of eIF4E in the sensorimotor neocortices 1 and 3 days after a lateral hemisection SCI, used as a model for Brown-Séquard syndrome. The function of an RBP depends on both its distribution sites within the cell and its phosphorylation states. Indeed, we found both to be affected after SCI. There was a distinct subcellular redistribution of eIF4E and phosphorylated-eIF4E was reduced, indicating that the eIF4E’s translation was disrupted. Upon identification and analysis of the mRNA cargo of eIF4E in uninjured sensorimotor neocortices, we found that eIF4E binds both Importin-13 (Ipo13) and Parvalbumin (Pv) mRNAs, indicating a role in their translation. Remarkably, eIF4E’s interaction with both Ipo13 and Pv mRNAs was disrupted 1 and 3 days after SCI, despite preservation of total Ipo13 and Pv mRNA levels. Finally, we detected a selective loss of expression of both IPO13 and PV proteins in projection neurons of sensorimotor neocortices, as well as their disrupted dendritic polarity. Since IPO13 is predominantly expressed in neocortical projection neurons and PV in a subset of neocortical interneurons, these data suggest a strong acute effect of SCI on neocortical microcircuitry. Taken together, these data indicate that neocortical eIF4E and a subset of mRNAs may be rapidly recruited to translational machinery after SCI to promote adaptive regeneration response of sensorimotor neurons.

In this review, we will highlight the importance of integrating neuroanatomical, clinical, electrophysiological, radiological, and functional imaging features in motor neuron diseases. The major concepts will be discussed through a case of a 69-year-old woman with progressive gait difficulties. Step by step, divided by sections, the clinical reasoning is explained, together with questions for consideration.

Myelin abnormalities exist in schizophrenia leading to the hypothesis that oligodendrocyte dysfunction plays a role in the pathophysiology of the disease. The expression of the mRNA for the peripheral myelin protein-22 (PMP-22) is decreased in schizophrenia and recent genetic evidence suggests a link between PMP-22 and schizophrenia. While PMP-22 mRNA is found in both rodent and human brain it has been generally thought that no protein expression occurs. Here we show that PMP-22 protein is present in myelin isolated from adult mouse and human brain. These results suggest that PMP-22 protein likely plays a role in the maintenance and function of central nervous system (CNS) myelin and provide an explanation for why altered PMP-22 expression may be pathophysiologically relevant in a CNS disorder such as schizophrenia.

Detection of a change in face is a socially important skill. Both event-related potential (ERP) and magnetoencephalographic (MEG) measurements were conducted using face stimuli presented in an oddball paradigm to investigate detection of a change in face identity and facial expression. In condition 1, a nontarget deviant neutral face was presented among standard happy faces. In condition 2, the same deviant neutral face was presented with a standard neutral face of another person. The task in both conditions was silent counting of a second deviant (face with glasses). Non-target deviants elicited more negative ERP and corresponding MEG responses than standards in both conditions. This negativity was strongest at lateral posterior channels around 280 ms. Responses to the same deviant neutral face differed in two conditions. Deviance-related negativity resembled auditory mismatch negativity (MMN). Different responses to the same deviant in the two conditions suggest the existence of a sensory-memory trace for the standard to which the deviant was compared.

There is growing clinical and neuropathologic evidence suggesting that cognitive decline in early Alzheimer’s disease (AD) is aggravated by a synergistic relationship between AD and cerebrovascular disease associated with cardiovascular risk factors such as diabetes and hypertension. Here we used the stereologic “Space Balls” method to investigate the relationships between AD pathology and cardiovascular risk factors in postmortem human brains of patients with hypertension and diabetes in two groups — one consisting of cases with AD diagnosis and one of cases without. Hippocampal CA1 and CA3 microvasculature length density estimates were generated to characterize quantitatively the contribution of cardiovascular risk factors to the severity of neuropathologic changes. Our main finding is that the mean and variance of length density values in the AD group were significantly increased from the non-AD group, regardless of the absence or presence of a cardiovascular risk factor. An additional finding is that in the AD group without a risk factor, dementia severity correlated with amount of length density change in the CA1 field—this correlation did not exist in the AD groups with risk factors. Our findings suggest a role for cardiovascular risk factors in quantifiable change of hippocampal CA1 field microvasculature, as well as suggest a possible role of cardiovascular risk factors in altering microvasculature pathology in the presence of AD.

Gangliosides are membrane glycosphingolipids bearing sialic acid residues. Within membranes, gangliosides are specifically enriched in highly organized domains, lipid rafts, and are attributed with diverse functions such as intercellular interactions, cell recognition, neurotransmission, and signal transduction. The highest concentration and variability of ganglioside structures are found in the human brain. Specific temporal and regional distribution of brain gangliosides has been reported; moreover, gangliosides may serve as markers of neurodevelopmental stages, aging and neurodegeneration. Brain ganglioside content and composition as well as ganglioside metabolism are altered in Alzheimer’s disease. It appears that the alterations of ganglioside metabolism leading to changes in membrane physico-chemical properties are not merely a consequence of primary pathology, but may also be involved in the early pathogenesis of Alzheimer’s disease through documented effects on APP proteolytic processing and amyloid aggregation. Investigations of glycolipid metabolic alterations which accompany neurodegenerative disorders provide insight into pathogenetic mechanisms and enable recognition of diagnostic markers as well as molecular structures acting as therapeutic tools interfering with cascade of pathological events.

Progress in understanding the genetic basis and pathophysiology of spinal muscular atrophy (SMA), along with continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels have resulted in several strategies that have been proposed as potential directions for efficient drug development. Here we provide an overview on the current status of the following approaches: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the very near future.

The recent development of the analytical techniques offers the unprecedented possibility to study simultaneously concentration of dozens of elements in the same biological matrix sample of 0.5–1.0 g (multielement profiles). The first part of this essay entitled “Think globally… An outline of trace elements in health and disease” aims to introduce the reader to the fascinating field of elements, there importance to our nutrition, their essentiality, deficiency, toxicity and bioavailability to the body and their overall role in health and disease, including the genetic metabolic impairments. In the second part of the essay entitled “… and act locally. The multielement profile of depression” we aimed to show the potential of such a hair multielement profile analysis for the study of human depression in a randomized, double blind, prospective, observational, cross-sectional, clinical, epidemiological, and analytical study. The preliminary results of this ongoing study lead us to put forward the hypothesis that the metabolic origin of depression may be due to some “energostat” failure, probably located in the thalamus, and activated by several essential element deficiencies.

It is commonly believed that the term hippocampus represents a shining example of inappropriate and fanciful anatomical naming, because this brain structure supposedly does not display any resemblance, striking or remote, to the little sea-horse fish known as hippocampus. The aim of this short historical notice is to demonstrate that, in fact, the hippocampus looks very much like the little sea-horse fish, as demonstrated by Gustav Retzius more than a century ago. However, to note this striking resemblance, one has to apply a proper method of anatomical dissection.