Institute for Clinical Neurobiology

Vienna, Austria

Institute for Clinical Neurobiology

Vienna, Austria
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Simon C.M.,Institute for Clinical Neurobiology | Jablonka S.,Institute for Clinical Neurobiology | Ruiz R.,University of Seville | Tabares L.,University of Seville | Sendtner M.,Institute for Clinical Neurobiology
Human Molecular Genetics | Year: 2010

Proximal spinal muscular atrophy (SMA) is caused by homozygous loss or mutation of the SMN1 gene on human chromosome 5. Depending on the levels of SMN protein produced from a second SMN gene (SMN2), different forms of the disease are distinguished. In patients with milder forms of the disease, type III or type IV SMA that normally reach adulthood, enlargement of motor units is regularly observed. However, the underlying mechanisms are not understood. Smn+/- mice, a mouse model of type III/IV SMA, reveal progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Loss of spinal motor neurons between 1 month and 12 months reaches 40%, whereas muscle strength is not reduced. In these animals, amplitude of single motor unit action potentials in the gastrocnemic muscle is increased more than 2-fold. Confocal analysis reveals pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF) is highly expressed in Schwann cells, we investigated its role for a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF results in reduced sprouting and decline of muscle strength in Smn+/- mice. These findings indicate that CNTF is necessary for a sprouting response and thus enhances the size of motor units in skeletal muscles of Smn+/- mice. This compensatory mechanism could guide the way to new therapies for this motor neuron disease. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


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.


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.


Hornburg D.,Max Planck Institute of Biochemistry | Drepper C.,University Hospital of Wuerzburg | Drepper C.,Institute for Clinical Neurobiology | Butter F.,Max Planck Institute of Biochemistry | And 4 more authors.
Molecular and Cellular Proteomics | Year: 2014

The fatal neurodegenerative disorders amyotrophic lateral sclerosis and spinal muscular atrophy are, respectively, the most common motoneuron disease and genetic cause of infant death. Various in vitro model systems have been established to investigate motoneuron disease mechanisms, in particular immortalized cell lines and primary neurons. Using quantitative mass-spectrometrybased proteomics, we compared the proteomes of primary motoneurons to motoneuron-like cell lines NSC-34 and N2a, as well as to non-neuronal control cells, at a depth of 10,000 proteins. We used this resource to evaluate the suitability of murine in vitro model systems for cell biological and biochemical analysis of motoneuron disease mechanisms. Individual protein and pathway analysis indicated substantial differences between mo-toneuron- like cell lines and primary motoneurons, especially for proteins involved in differentiation, cytoskeleton, and receptor signaling, whereas common metabolic pathways were more similar. The proteins associated with amyotrophic lateral sclerosis also showed distinct differences between cell lines and primary motoneurons, providing a molecular basis for understanding fundamental alterations between cell lines and neurons with respect to neuronal pathways with relevance for disease mechanisms. Our study provides a proteomics resource for motoneuron research and presents a paradigm of how mass-spectrometry-based proteomics can be used to evaluate disease model systems. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Wiese S.,Institute for Clinical Neurobiology | Wiese S.,Ruhr University Bochum | Herrmann T.,Institute for Clinical Neurobiology | Drepper C.,Institute for Clinical Neurobiology | And 6 more authors.
Nature Protocols | Year: 2010

Cultured spinal motoneurons are a valuable tool for studying the basic mechanisms of axon and dendrite growth and also for analyses of pathomechanisms underlying diseases like amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). As motoneurons in the developing spinal cord of mice constitute only a minor population of neurons, these cells need to be enriched in order to study them in the absence of contaminating neuronal and non-neuronal cells. Here, we describe a protocol for the isolation and in vitro cultivation of embryonic primary motoneurons from individual mouse embryos. Tissue dissection, cell isolation and a p75NTR-antibody-based panning technique, which highly enriches motoneurons within <8 h are described. This protocol is aimed to provide an alternative to the established FACS-based protocols describing p75NTR-based enrichments of neurons. This protocol will help in facilitating the research on molecular mechanisms underlying motoneuron development, survival and disease mechanisms. © 2009 Nature Publishing Group.


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.


Attems J.,Northumbria University | Ittner A.,University of Sydney | Jellinger K.,Institute for Clinical Neurobiology | Nitsch R.M.,University of Zürich | And 5 more authors.
Journal of Neural Transmission | Year: 2011

Neuropathological features in Alzheimer's Disease (AD) include the presence of hyperphosphorylated forms of the microtubule-associated tau protein (tau) in hippocampal neurones. Numerous studies indicate a neuroprotective effect of calcium-binding proteins (Ca2+ binding proteins) in neurodegenerative diseases (e.g., AD). Secretagogin is a newly described Ca2+ binding protein that is produced by pyramidal neurones of the human hippocampus. Recently, secretagogin expressing hippocampal neurones were demonstrated to resist tau-induced pathology in AD in contrast to the majority of neighbouring neurones. This suggested a neuroprotective effect of secretagogin in hippocampal neurones. Here, we investigated secretagogin expression in wild type (wt) mice as well as in hemizygous and homozygous P301L tau transgenic (tg) mice, which show pronounced and widespread tau pathology in hippocampal neurones. Secretagogin expression was analyzed at the immunohistochemical and biochemical levels in brains of age-matched wt and hemi- and homozygous tau tg mice. In wt mice hippocampal secretagogin-immunoreactive neurones were invariably detected, while immunoreactivity was much lower (P < 0.001) in tau tg mice. Of note, hippocampal secretagogin immunoreactivity was absent in 62.5% of homozygous tau tg mice. In line with this finding, Western blot analysis demonstrated a significant reduction in protein expression levels of secretagogin in homozygous tau tg compared to wt mice. Our results suggest that increased levels of tau negatively influence secretagogin expression in the hippocampus of tau tg mice. © 2011 Springer-Verlag.


Attems J.,Northumbria University | Thal D.R.,University of Ulm | Jellinger K.A.,Institute for Clinical Neurobiology
Biochemical Society Transactions | Year: 2012

The stepwise progression of tau pathology [NFTs (neurofibrillary tangles) and NTs (neuropil threads)] in AD (Alzheimer's disease) is generally assumed to begin in the transentorhinal region (entorhinal stage) from which it progresses to the hippocampus (limbic stage) and to neocortical regions (neocortical stage). This stepwise progression is reflected in the NFT Braak stages. However, it has been shown recently that tau pathology is frequently seen in subcortical nuclei, in particular the LC (locus coeruleus) in over 90% of individuals under 30 years of age, suggesting that AD-associated tau pathology begins in the LC and not in the transentorhinal region. On the other hand, onlyminimal amounts of tau pathology are seen in the LC in cases with considerable entorhinal tau pathology, while the severity of tau pathology in the LC significantly increases with increasing NFT Braak stages. These findings suggest that the LC becomes increasingly involved during AD progression rather than representing the site initially affected. Further studies are warranted to answer the question of whether tau pathology in the LC of young individuals is associated with AD or whether it rather reflects non-specific neuronal damage. ©The Authors Journal compilation ©2012 Biochemical Society.


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.


PubMed | Institute for Clinical Neurobiology
Type: Journal Article | Journal: Human molecular genetics | Year: 2010

Axonal transport and translation of beta-actin mRNA plays an important role for axonal growth and presynaptic differentiation in many neurons including hippocampal, cortical and spinal motor neurons. Several beta-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 beta-actin translocation. hnRNP-R and beta-actin mRNA are colocalized in axons. Recombinant hnRNP-R interacts directly with the 3-UTR of beta-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 beta-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 beta-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 beta-actin mRNA translocation plays an essential physiological role for axon growth and presynaptic differentiation.

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