E. Petrasch-parwez - Academia.edu (original) (raw)

Papers by E. Petrasch-parwez

Frontiers in Cell and Developmental Biology, Jan 12, 2021

The indusium griseum (IG) is a cortical structure overlying the corpus callosum along its anterio... more The indusium griseum (IG) is a cortical structure overlying the corpus callosum along its anterior-posterior extent. It has been classified either as a vestige of the hippocampus or as an extension of the dentate gyrus via the fasciola cinerea, but its attribution to a specific hippocampal subregion is still under debate. To specify the identity of IG neurons more precisely, we investigated the spatiotemporal expression of calbindin, secretagogin, Necab2, PCP4, and Prox1 in the postnatal mouse IG, fasciola cinerea, and hippocampus. We identified the calcium-binding protein Necab2 as a first reliable marker for the IG and fasciola cinerea throughout postnatal development into adulthood. In contrast, calbindin, secretagogin, and PCP4 were expressed each with a different individual time course during maturation, and at no time point, IG or fasciola cinerea principal neurons expressed Prox1, a transcription factor known to define dentate granule cell fate. Concordantly, in a transgenic mouse line expressing enhanced green fluorescent protein (eGFP) in dentate granule cells, neurons of IG and fasciola cinerea were eGFP-negative. Our findings preclude that IG neurons represent dentate granule cells, as earlier hypothesized, and strongly support the view that the IG is an own hippocampal subfield composed of a distinct neuronal population.

The EMBO Journal, Mar 18, 2019

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the bra... more Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domaincontaining transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for diseasemodifying strategies in proteinopathies.

Cognitive Neuroscience, 2010

This article may be used for research, teaching, and private study purposes. Any substantial or s... more This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

InTech eBooks, Dec 19, 2012

The Amygdala-A Discrete Multitasking Manager 386 results in a rat transgenic for Huntington's dis... more The Amygdala-A Discrete Multitasking Manager 386 results in a rat transgenic for Huntington's disease (tgHD), which is unique in its limbic impact (Niescery et al., 2009; Petrasch-Parwez et al., 2007), and add recent results in the respective areas of the human HD brain (Petrasch-Parwez et al., 2012).

From Pathophysiology to Treatment of Huntington's Disease [Working Title]

Neuropathology of Huntington’s disease (HD) presents with progredient neuronal cell loss mainly i... more Neuropathology of Huntington’s disease (HD) presents with progredient neuronal cell loss mainly in the striatum, but also in multiple other brain areas suggesting HD as a multisystem neurodegenerative disorder. Mutant huntingtin aggregates are the characteristic hallmark of HD. The aggregates are misfolded proteins varying in location, form, size and structural composition indicating a complex involvement in neurotoxicity. The question if and how the aggregates and many interacting protein partners may lead to cell death is continuously a matter of debate. The role of mutant huntingtin is more than ever of paramount importance as present genetic therapeutic approaches try to target downregulation of the Huntingtin gene expression and/or lowering the corresponding protein. In this context—and these aspects are focussed—it is of crucial interest to elucidate the regional distribution as well as the cellular and subcellular localization of aggregates in established animal models of HD ...

IntechOpen eBooks, Oct 26, 2022

Neuropathology of Huntington's disease (HD) presents with progredient neuronal cell loss mainly i... more Neuropathology of Huntington's disease (HD) presents with progredient neuronal cell loss mainly in the striatum, but also in multiple other brain areas suggesting HD as a multisystem neurodegenerative disorder. Mutant huntingtin aggregates are the characteristic hallmark of HD. The aggregates are misfolded proteins varying in location, form, size and structural composition indicating a complex involvement in neurotoxicity. The question if and how the aggregates and many interacting protein partners may lead to cell death is continuously a matter of debate. The role of mutant huntingtin is more than ever of paramount importance as present genetic therapeutic approaches try to target downregulation of the Huntingtin gene expression and/or lowering the corresponding protein. In this context-and these aspects are focussed-it is of crucial interest to elucidate the regional distribution as well as the cellular and subcellular localization of aggregates in established animal models of HD and in affected HD brains.

Journal of Neurology, Neurosurgery, and Psychiatry, Aug 29, 2012

Background Huntington disease (HD) is characterised by cognitive impairment, motor dysfunction an... more Background Huntington disease (HD) is characterised by cognitive impairment, motor dysfunction and psychiatric symptoms, the latter presenting as apathy, irritability, outburst, anxiety and depression. To date neuropathological correlates for psychiatric affection have been poorly investigated in HD. In the basal forebrain two systems represent a complex morphological substrate for emotion-associated functions. The ventral striatum integrates emotional, cognitive, sensory and motor information. The extended amygdala is associated with fear, hormonal responses, stress and it is involved in addiction. Methods In order to evaluate their impact for psychiatric affection in HD, we investigated the distribution of huntingtin aggregates and the associated neuropathology in the subareas of both systems in human HD brains by light and electron microscopical EM48-immunohistochemistry. Results Huntingtin aggregates are abundantly patch-like expressed in the nucleus accumbens (with no difference in Calbindin-poor nor Calbindin-rich areas), ventral parts of the caudate and putamen and the olfactory tubercle, all of which areas belonging to the ventral striatum. In contrast, in the dorsal motor-associated striatum, an area exhibiting major atrophy in HD, aggregates are sparse. The subregions of the extended amygdala, the bed nuclei of the stria terminalis, the interstitial nucleus of the posterior part of the anterior commissure and the central amygdaloid nuclei also show prominent huntingtin accumulation. Electron microscopically, the aggregates are mainly detected in the neuropil, whereas intranuclear localisation occurs occasionally. Conclusions Differential affection of the two limbic forebrain systems may help to elucidate emotional regulatory and psychiatric aspects of HD, and it may also yield information on the role of huntingtin aggregates in HD pathogenesis.

PLOS ONE, Feb 20, 2013

<p>Blinded quantification of neurons after cresyl violet or NeuN staining revealed a signif... more <p>Blinded quantification of neurons after cresyl violet or NeuN staining revealed a significantly higher number of intact neurons in the striatum and in the motor cortex of DMF treated mice.</p

Human Molecular Genetics, 2020

The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed... more The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These pat...

neurogenetics, 2009

Canine generalized progressive retinal atrophy (gPRA) is characterized by continuous degeneration... more Canine generalized progressive retinal atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 (CCDC66) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease. The insertion is present in all affected dogs in the homozygous state as well as in all obligatory mutation carriers in the heterozygous state. The CCDC66 gene is evolutionarily conserved in different vertebrate species and exhibits a complex pattern of differential RNA splicing resulting in various isoforms in the retina. Immunohistochemically, CCDC66 protein is detected mainly in the inner segments of photoreceptors in mouse, dog, and man. The affected Schapendoes retina lacks CCDC66 protein. Thus this natural canine model for gPRA yields superior potential to understand functional implications of this newly identified protein including its physiology, and it opens new perspectives for analyzing different aspects of the general pathophysiology of gPRA.

Background: Cardiomyocyte (CM) STAT3 plays a pivotal role in various forms of cardiac pathophysio... more Background: Cardiomyocyte (CM) STAT3 plays a pivotal role in various forms of cardiac pathophysiology affecting CMs and, in a paracrine manner non-cardiomyocytes. Objective: We evaluated the role of putative STAT3-dependent miRNAs with regard to CM phenotype and secretome. Methods and Results: miCHIP and quantitative real-time PCR analysis revealed elevated cardiac expression of miR-199a in mice with a CM restricted knock out of STAT3 (qRT-miR-PCR: + 7.4 fold). Lentiviral-mediated RNAi against STAT3 in CMs increased pri-miR-199a (16-fold; p Conclusion: Protein turnover, growth and secretory activity of CMs are modulated by STAT3 dependent expression of microRNA-199a. The miR-199a-induced alteration of the cardiomyocytic secretome causes fibroblast proliferation and endothelial dysfunction in a paracrine fashion, most likely by enhancing endogenous ADMA levels.

Journal of Neural Transmission, 2009

6th German Parkinson Congress of the German Parkinson Society (DPG) Marburg, Germany, March 5–7, ... more 6th German Parkinson Congress of the German Parkinson Society (DPG) Marburg, Germany, March 5–7, 2009 Published online: 24 January 2009 Springer-Verlag 2009

The Journal of Neuroscience, 2000

We describe the identification and initial characterization of neurobeachin, a neuron-specific mu... more We describe the identification and initial characterization of neurobeachin, a neuron-specific multidomain protein of 327 kDa with a high-affinity binding site (K d , 10 nM) for the type II regulatory subunit of protein kinase A (PKA RII). Neurobeachin is peripherally associated with pleomorphic tubulovesicular endomembranes near the trans sides of Golgi stacks and throughout the cell body and cell processes. It is also found in a subpopulation of synapses, where it is concentrated at the postsynaptic plasma membrane. In live cells, perinuclear neurobeachin is dispersed by brefeldin A (BFA) within 1 min, and in permeabilized cells a recruitment of neurobeachin from cytosol to Golgi-near membranes is stimulated by GTP␥S and prevented by brefeldin A. Spots of neurobeachin recruitment are close to but distinct from recruitment sites of COP-I, AP-1, and AP-3 coat proteins involved in vesicle budding. These observations indicate that neurobeachin binding to membranes close to the trans-Golgi requires an ADP-ribosylation factor-like GTPase, possibly in association with a novel type of protein coat. A neurobeachin isoform that does not bind RII, beige-like protein (BGL), is expressed in many tissues. Neurobeachin, BGL, and ϳ10 other mammalian gene products share a characteristic C-terminal BEACH-WD40 sequence module, which is also present in gene products of invertebrates, plants, protozoans, and yeasts, thus defining a new protein family. The prototype member of this family of BEACH domain proteins, lysosomal trafficking regulator (LYST), is deficient in genetic defects of protein sorting in lysosome biogenesis (the beige mouse and Chediak-Higashi syndrome). Neurobeachin's subcellular localization, its coat proteinlike membrane recruitment, and its sequence similarity to LYST suggest an involvement in neuronal post-Golgi membrane traffic, one of its functions being to recruit protein kinase A to the membranes with which it associates.

The Journal of Neuroscience, 2003

Compensatory mechanisms after genetic manipulations have been documented extensively for the nerv... more Compensatory mechanisms after genetic manipulations have been documented extensively for the nervous system. In many cases, these mechanisms involve genetic regulation at the transcription or expression level of existing isoforms. We report a novel mechanism by which single neurons compensate for changes in network connectivity by retuning their intrinsic electrical properties. We demonstrate this mechanism in the inferior olive, in which widespread electrical coupling is mediated by abundant gap junctions formed by connexin 36 (Cx36). It has been shown in various mammals that this electrical coupling supports the generation of subthreshold oscillations, but recent work revealed that rhythmic activity is sustained in knockouts of Cx36. Thus, these results raise the question of whether the olivary oscillations in Cx36 knockouts simply reflect the status of wild-type neurons without gap junctions or the outcome of compensatory mechanisms. Here, we demonstrate that the absence of Cx36 results in thicker dendrites with gap-junction-like structures with an abnormally wide interneuronal gap that prevents electrotonic coupling. The mutant olivary neurons show unusual voltage-dependent oscillations and an increased excitability that is attributable to a combined decrease in leak conductance and an increase in voltagedependent calcium conductance. Using dynamic-clamp techniques, we demonstrated that these changes are sufficient to transform a wild-type neuron into a knockout like neuron. We conclude that the absence of Cx36 in the inferior olive is not compensated by the formation of other gap-junction channels but instead by changes in the cytological and electroresponsive properties of its neurons, such that the capability to produce rhythmic activity is maintained.

Aktuelle Neurologie, 2005

Journal of Cell Biology, 1998

We report the identification and initial characterization of paralemmin, a putative new morphoreg... more We report the identification and initial characterization of paralemmin, a putative new morphoregulatory protein associated with the plasma membrane. Paralemmin is highly expressed in the brain but also less abundantly in many other tissues and cell types. cDNAs from chicken, human, and mouse predict acidic proteins of 42 kD that display a pattern of sequence cassettes with high inter-species conservation separated by poorly conserved linker sequences. Prenylation and palmitoylation of a COOH-terminal cluster of three cysteine residues confers hydrophobicity and membrane association to paralemmin. Paralemmin is also phosphorylated, and its mRNA is differentially spliced in a tissue-specific and developmentally regulated manner. Differential splicing, lipidation, and phosphorylation contribute to electrophoretic heterogeneity that results in an array of multiple bands on Western blots, most notably in brain. Paralemmin is associated with the cytoplasmic face of the plasma membranes o...

Journal of Neurology, Neurosurgery & Psychiatry, 2010

BMC medical genetics, Jan 28, 2005

For allergic disorders, the increasing prevalence over the past decade has been attributed in par... more For allergic disorders, the increasing prevalence over the past decade has been attributed in part to the lack of microbial burden in developed countries ('hygiene hypothesis'). Variation in genes encoding toll-like receptors (TLRs) as the receptor system for the first innate immune response to microbial stimuli has been implicated in various inflammatory diseases. We evaluated here the role of a coding variation, Ser249Pro, in the TLR6 gene in the pathogenesis of asthma, atopic dermatitis (AD) and chronic obstructive pulmonary disease (COPD). Genotyping of the Ser249Pro polymorphism in 68 unrelated adult patients and 132 unrelated children with asthma, 185 unrelated patients with COPD, 295 unrelated individuals with AD and 212 healthy control subjects was performed by restriction enzyme digestion. We found a weak association of the 249Ser allele with childhood asthma (p = 0.03). Yet, significance was lost after Bonferroni correction. No association was evident for AD or COP...