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Zanucco E.,Max Planck Institute of Biochemistry | El-Nikhely N.,Max Planck Institute for Heart and Lung Research | Gotz R.,University of Wurzburg | Gotz R.,Institute for Clinical Neurobiology | And 8 more authors.
Journal of Biological Chemistry | Year: 2014

Background: The regulation of RAF kinases is a highly complex process.Results: Loss of B-RAF in alveolar epithelial type II cells does not inhibit oncogenic C-RAF BxB-driven lung tumor initiation but diminishes MAPK signaling and tumor growth.Conclusion: B-RAF cooperates with oncogenic C-RAF BxB in lung tumorigenesis.Significance: Inhibition of RAFs dimerization might be a new therapeutic option for oncogenic C-RAF-driven tumors. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Attems J.,Northumbria University | Jellinger K.,Institute for Clinical Neurobiology | Thal D.R.,University of Ulm | Van Nostrand W.,State University of New York at Stony Brook
Neuropathology and Applied Neurobiology | Year: 2011

J. Attems, K. Jellinger, D. R. Thal and W. Van Nostrand (2011) Neuropathology and Applied Neurobiology37, 75-93 Sporadic cerebral amyloid angiopathyCerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-β protein (Aβ) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aβ refers to Aβ depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aβ depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aβ40 and Aβ42 in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aβ precursor protein show parenchymal Aβ and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aβ enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aβ, respectively. We suggest that pericapillary Aβ represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aβ. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society. Source


Attems J.,Northumbria University | Thomas A.,Northumbria University | Jellinger K.,Institute for Clinical Neurobiology
Neuropathology and Applied Neurobiology | Year: 2012

Aim: Recent studies indicate that tau pathology in Alzheimer's disease (AD) does not initially manifest in the cerebral cortex but in selected subcortical nuclei, in particular the locus ceruleus (LC). In this study we correlate both olfactory and brainstem tau pathology with neuritic Braak stages. Methods: We examined 239 unselected autopsy cases (57.3% female, 42.7% male; aged 55-102, mean 82.8±9.7 SD years; AD, 44.8%; non-demented controls, 31.8%; Parkinson's disease, 5.0%; dementia with Lewy bodies, 2.5%; AD+Lewy body disease, 15.9%). Neuropathological examination according to standardized methods included immunohistochemistry and semiquantitative assessment of tau lesions in LC, substantia nigra (SN), dorsal motor nucleus of nervus vagus (dmX), and olfactory bulb (OB). Results: In Braak stage 0, tau pathology (usually very sparse pretangle material) was seen in the OB in 52.9% and in the SN/LC in 44%. The prevalence of OB and subcortical tau pathology increased with increasing Braak stages and reached 100% in OB, SN and LC and 95.2% in dmX in Braak stage VI, respectively. The severity of tau pathology in OB and subcortical nuclei significantly (P<0.001) correlated with Braak stages and these correlations remained statistically significant when controlling for concomitant α-synuclein pathology in the respective regions. Conclusions: Our finding of an increase in both prevalence and severity of OB, LC, SN and dmX tau pathology in AD with increasing Braak stages suggests that these regions become increasingly involved during AD progression rather than representing sites initially affected by AD-associated tau pathology. © 2011 British Neuropathological Society. Source


Zellner M.,Medical University of Vienna | Baureder M.,Medical University of Vienna | Rappold E.,Otto Wagner Spital | Bugert P.,Red Cross | And 9 more authors.
Journal of Proteomics | Year: 2012

Monoamine oxidase-B (Mao-B) catalysing the breakdown of the neurotransmitter dopamine, is known to be involved in the pathophysiology of Parkinson's (PD) and Alzheimer's disease (AD). Increased brain Mao-B activity is associated with AD. This alteration can also be seen in platelets, albeit the cause has hitherto remained elusive. To gain a deeper understanding of the etiology of AD, the platelet proteome was characterised, (2D DIGE pH6-9, including Mao-B) from 150 individuals: 34. AD, 13 vascular dementia, 15 non-demented PD patients, 49 matched controls, 18 oldest old and 21 young individuals. One significant change was noted after applying false discovery rate with the upregulation of the Mao-B expression (30% adjusted P value < 0.001; effect size 1.31) in AD compared to age- and sex-matched controls. In contrast, Mao-B levels were unchanged in PD to matched controls. Western blot and mRNA analyses verified these findings. Moreover, Mao-B concentration correlated with age in the cognitive healthy individuals (r = 0.53; P < 0.001) and PD patients but not in those suffering from AD (r = - 0.03; P = 0.874). Mao-B activity correlated with the increased Mao-B protein expression in AD (r = 0.81; P = 0.016). We suggest that Mao-B platelet protein level may serve as a biomarker for age-related dementia, especially AD. © 2012 Elsevier B.V. Source


Glinka M.,Institute for Clinical Neurobiology | Herrmann T.,Institute for Clinical Neurobiology | Funk N.,Institute for Clinical Neurobiology | Havlicek S.,Institute for Clinical Neurobiology | And 5 more authors.
Human Molecular Genetics | Year: 2010

Axonal transport and translation of β-actin mRNA plays an important role for axonal growth and presynaptic differentiation in many neurons including hippocampal, cortical and spinal motor neurons. Several β-actin mRNA-binding and transport proteins have been identified, including ZBP1, ZBP2 and hnRNP-R. hnRNP-R has been found as an interaction partner of the survival motor neuron protein that is deficient in spinal muscular atrophy. Little is known about the function of hnRNP-R in axonal β-actin translocation. hnRNP-R and β-actin mRNA are colocalized in axons. Recombinant hnRNP-R interacts directly with the 3′-UTR of β-actin mRNA. We studied the role of hnRNP-R in motor neurons by knockdown in zebrafish embryos and isolated mouse motor neurons. Suppression of hnRNP-R in developing zebrafish embryos results in reduced axon growth in spinal motor neurons, without any alteration in motor neuron survival. ShRNA-mediated knockdown in isolated embryonic mouse motor neurons reduces β-actin mRNA translocation to the axonal growth cone, which is paralleled by reduced axon elongation. Dendrite growth and neuronal survival were not affected by hnRNP-R depletion in these neurons. The loss of β-actin mRNA in axonal growth cones of hnRNP-R-depleted motor neurons resembles that observed in Smn-deficient motor neurons, a model for the human disease spinal muscular atrophy. In particular, hnRNP-R-depleted motor neurons also exhibit defects in presynaptic clustering of voltage-gated calcium channels. Our data suggest that hnRNP-R-mediated axonal β-actin mRNA translocation plays an essential physiological role for axon growth and presynaptic differentiation. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. Source

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