Band 3, Heft 2

Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

Entorhinal verrucae are unique, small elevations on the surface of entorhinal cortex, formed due to distinctive clustering of large neurons in entorhinal layer II. In Alzheimer’s disease, the verrucae atrophy as a result of neurofibrillary tangle formation and concomitant neuronal loss. Previously, we found significant decreases in verrucae height, width, surface area, and volume even in the mildest stage of Alzheimer’s disease. In this report, we introduce a new method for analyzing verrucae prominence using measures of their curvature. Smoothed surfaces and curvatures were generated using FreeSurfer (http://surfer.nmr.mgh.harvard.edu) from 100 μm3 ex vivo MRI isosurfaces. We examined the positive and negative components of mean curvature AreaNorm(H+/-) and Gaussian curvature AreaNorm(K +/−) in entorhinal cortex. A significant difference was found between entorhinal (n=10) and non-entorhinal cortices (n=9) for both AreaNorm(H+/-) and AreaNorm(K +/−). We also validated our curvature analysis through a comparison with previously published verrucae measures derived from manual labels of individual verrucae. A significant positive correlation was found between mean verrucae height and AreaNorm(H+/-). Both mean verrucae height and volume were significantly positively correlated with AreaNorm(K +/−). These results demonstrate that K and H are accurate metrics for detecting the presence or absence of entorhinal verrucae. Curvature analysis may be a useful and sensitive technique for detecting local surface changes in entorhinal cortex.

PTEN (phosphatase and tensin homologue deleted in chromosome 10) was first identified as a candidate tumour suppressor gene located on chromosome 10q23. It is considered as one of the most frequently mutated genes in human malignancies. Emerging evidence shows that the biological function of PTEN extends beyond its tumour suppressor activity. In the central nervous system PTEN is a crucial regulator of neuronal development, neuronal survival, axonal regeneration and synaptic plasticity. Furthermore, PTEN has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Recently increased attention has been focused on PTEN as a potential target for the treatment of brain injury and neurodegeneration. In this review we discuss the essential functions of PTEN in the central nervous system and its involvement in neurodegeneration.

All-trans-retinoic acid (ATRA) is a vitamin A derivative that is important in neuronal patterning, survival, and neurite outgrowth. Neuroprotective effects of ATRA in ischemia have been demonstrated but its effects on glial swelling are not known. We investigated the relatively acute effects of ATRA on cell swelling in ischemic injury and on key features hypothesized to contribute to cell swelling including increased reactive oxygen species/reactive nitrogen species (ROS/RNS), depolarization of the inner mitochondrial membrane potential (ΔΨm), and increased intracellular calcium ([Ca2+]i). C6 glial cultures were subjected to 5 hr oxygen-glucose deprivation (OGD). ATRA was added to separate groups after the end of OGD. OGD increased cell volume by 43%, determined at 90 min after the end of OGD, but this increase was significantly attenuated by ATRA. OGD induced an increase in ROS/RNS production in the whole cell and mitochondria, as assessed by the fluorescent dyes CM-H2DCFDA and MitoTracker CM-H2-XROS at the end of OGD. The increase in mitochondrial ROS, but not cellular ROS, was significantly attenuated by ATRA. OGD also induced a 67% decline in mitochondrial ΔΨm but this decline was significantly attenuated by ATRA. OGD-induced increase in [Ca2+]i was also significantly attenuated by ATRA. Taken together with our previous results where calcium channel blockers reduced cell swelling, the effects of ATRA in attenuating swelling are possibly mediated through its effects in regulating [Ca2+]i. Considering the paucity of agents in attenuating brain edema in ischemia, ATRA has the potential to reduce brain edema and associated neural damage in ischemic injury.

Tourette syndrome (TS) is a disabling neuropsychiatric disorder characterised by persistent motor and vocal tics. TS is a highly comorbid state, hence, patients might experience anxiety, obsessions, compulsions, sleep abnormalities, depression, emotional liability, learning problems, and attention deficits in addition to tics. In spite of its complex heterogeneous genetic aetiology, recent studies highlighted a strong link between TS and genetic lesions in the HDC (L-histidine decarboxylase) gene, which encodes the enzyme that synthetises histamine, and the SLITRK1 (SLIT and TRK-like family member 1) gene, which encodes a transmembrane protein that was found to regulate neurite outgrowth. In addition to validating the contribution of a specific genetic aberration to the development of a particular pathology, animal models are crucial to dissect the function of disease-linked proteins, expose disease pathways through examination of genetic modifiers and discover as well as assess therapeutic strategies. Mice with a knockout of either Hdc or Slitrk1 exhibit anxiety and those lacking Hdc, display dopamine agonist-triggered stereotypic movements. However, the mouse knockouts do not spontaneously display tics, which are recognised as the hallmark of TS. In this review, we explore the features of the present genetic animal models of TS and identify reasons for their poor resemblance to the human condition. Importantly, we highlight ways forward aimed at developing a valuable genetic model of TS or a model that has good predictive validity in developing therapeutic drugs for the treatment of tics, hence potentially accelerating the arduous journey from lab to clinic.

Recent studies have investigated the association between serotonin transporter gene promoter (5-HTTLPR) functional polymorphisms and attentional biases to threat, a cognitive mechanism that probably contributes to the development and maintenance of anxiety. The present study genotyped a sample of N = 141 healthy volunteers for an insertion/deletion polymorphism and the rs25531 single-nucleotide polymorphism in 5-HTTLPR. In order to investigate attentional biases to threat, we used a probe discrimination task in which the gaze direction of centrally presented fearful or neutral faces endogenously cued attention. The results indicated no significant differences in attentional biases to threat between 5-HTTLPR genotype groups. However, we found that carriers of two low-expressing alleles (i.e., S or LG) of 5-HTTLPR displayed a significant slowing of responses across trials with fearful compared to neutral faces. This effect may indicate that fearful faces triggered increased emotional arousal in these genotypes, which may have interfered with the processing of gaze direction and spatial cuing. These results suggest that using fearful faces as endogenous spatial cues may be problematic in genotypes associated with facilitated emotional arousal to these stimuli, and underscore the hypothesis that 5-HTTLPR specifically influences automatic rather than consciously-controlled processes of attention.

A tight functional link between the central nervous and peripheral immune system closely related to the activity of NF-κB transcription factor has been evidenced in numerous brain pathological conditions. One of the most instructive examples is a prion neuroinvasion and the development of transmissible spongioform encephalopathy (TSE) or prion diseases. The failure of peripherally administrated prions to elicit disease in immune-deficient mice indicates that preserved organ microarchitecture is crucial for TSE pathogenesis and it seems to go through topographic relationships between follicular dendritic cells and sympathetic endings in lymphoid organs. New insight into the molecular requirements for follicular dendritic cell (FDC) development in NF-κB p52 deficient mice highlights the role of NF-κB transcription factor in prion disease progression. However, adoptive transfer of wild type bone marrow cells (NF-κB +/+ background) into p52 deficient animals (NF-κB -/- background) does not correct the FDC defect. RT-PCR analysis of the expression level of mRNA for LTa, LTb, TNFRI and BLC of the splenic cells from p52/NF-κB mutant/wt BM chimera did not reveal major changes compared to wt/wt BM chimeras, indicating that their normal expression within splenic tissue does not assure for complete restoration of the FDC network in p52/NF-κB mutant. This implies that the distance between FDCs and splenic nerve terminals around the central arteriole is longer and could interfere with prion spreading in lymphoid organs prior to neuroinvasion. In light of the fact that prion neuroinvasion highly depends on the physical distance between sympathetic nerve endings and FDCs dendritic extensions, it is not hard to imagine that this could be the way to approach the problem of prion diseases development.

Individuals with autism spectrum disorder (ASD) have previously been shown to have significantly augmented and prolonged event-related potentials (ERP) to irrelevant visual stimuli compared to controls at both early and later stages (e.g., N200, P300) of visual processing and evidence of an overall lack of stimulus discrimination. Abnormally large and indiscriminative cortical responses to sensory stimuli may reflect cortical inhibitory deficits and a disruption in the excitation/inhibition ratio. Low-frequency (≤ 1HZ) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits. It was our prediction that after 12 sessions of low-frequency rTMS applied bilaterally to the dorsolateral prefrontal cortices in individuals with ASD there would be a significant improvement in ERP indices of selective attention evoked at later (i.e., 200–600 ms) stages of attentional processing as well as an improvement in motor response error rate. We assessed 25 participants with ASD in a task of selective attention using illusory figures before and after 12 sessions of rTMS in a controlled design where a waiting-list group of 20 children with ASD performed the same task twice. We found a significant improvement in both N200 and P300 components as a result of rTMS as well as a significant reduction in response errors. We also found significant reductions in both repetitive behavior and irritability according to clinical behavioral questionnaires as a result of rTMS. We propose that rTMS has the potential to become an important therapeutic tool in ASD research and treatment.

Central nervous system (CNS) injuries affect all levels of society indiscriminately, resulting in functional and behavioral deficits with devastating impacts on life expectancies, physical and emotional wellbeing. Considerable literature exists describing the pathophysiology of CNS injuries as well as the cellular and molecular factors that inhibit regrowth and regeneration of damaged connections. Based on these data, numerous therapeutic strategies targeting the various factors of repair inhibition have been proposed and on-going assessment has demonstrated some promising results in the laboratory environ. However, several of these treatment strategies have subsequently been taken into clinical trials but demonstrated little to no improvement in patient outcomes. As a result, options for clinical interventions following CNS injuries remain limited and effective restorative treatment strategies do not as yet exist. This review discusses some of the current animal models, with focus on nonhuman primates, which are currently being modeled in the laboratory for the study of CNS injuries. Last, we review the current understanding of the mechanisms underlying repair/regrowth inhibition and the current trends in experimental treatment strategies that are being assessed for potential translation to clinical applications.

Accumulating evidence from the field of neuroscience indicates a crucial role for epigenetic regulation of gene expression in development and aging of nervous system and suggests that aberrations in the epigenetic machinery are involved in the etiology of psychiatric disorders. Epidemiologic evidence on epigenetics in psychiatry, however, is currently very sparsely available, but is consistent with a mediating role for epigenetic mechanisms in bringing together inherited and acquired risk factors into a neurodevelopmental etiological model of psychiatric disorders. Here, we review evidence from the epidemiological and neuroscience literature, and aim to converge the evidence into an etiological model of psychiatric disorders that encompasses environmental, genetic and epigenetic contributions. Given the dynamic nature of the epigenetic machinery and the potential reversibility of epigenetic modifications, future well-designed interdisciplinary and translational studies will be of key importance in order to identify new targets for prevention and therapeutic strategies.

Gangliogliomas are well differentiated and slowly growing neuroepithelial tumors composed of neoplastic ganglion cells and neoplastic glial cells corresponding mostly to the World Health Organization grade I tumors. However, some of these tumors disclose histologically more malignant glial component and correspond to grade II or grade III tumors. We report a case of left temporal lobe tumor in a 42-year-old woman fulfilling the diagnostic criteria for atypical (grade II) ganglioglioma with high Ki-67 proliferation index and p53 immunoreactive tumor cells. In spite of gross total removal of the tumor, it recurred eight months after surgery. Histopathological examination of the recurrent tumor revealed that it had undergone malignant transformation into a glioblastoma. This case indicates that gangliogliomas with high Ki-67 proliferating index and p53 immunoreactivity should be carefully monitored for recurrence and malignant progression regardless of their morphological grading and seemingly total surgical removal.

Pluripotent stem cells hold great promise for the generation of patient-specific cells for disease modeling and regenerative medicine. Focusing on a recent study reporting the successful generation of midbrain dopaminergic neurons and their efficient grafting in animal models of Parkinson’s disease, I discuss how crosstalk between basic and applied stem cell research more generally paves the road toward clinical translation.