http://www.mdpi.com/journal/ijms/special_issues/molecular-neuropathology/ Dear Colleagues, During the recent years, considerable progress has been achieved in molecular genetics, pathogenesis and pathology of many nervous system disorders, based on new and modern technologies and animal models. In the field of tumors of the CSN, the new 2007 classification, based on modern molecular genetics, immunocytochemistry and proteomics, has provided deeper insights into the pathogenesis and molecular pathobiology of CNS malignancies and has listed several new entities to the existing grading system, thus broadening the diagnostic spectrum and prognostic factors. Modern research in inflammatory disorders of the nervous system has been focused on different types of multiple sclerosis (MS), their molecular and immunopathology, as well as on new molecular genetic findings and animal models of MS and related disorders, such as neuromyelitis optica and immun-mediated neuropathies, neuro-AIDS (CNS-HIV), and the relations between neuroinflammation and neurodegeneration. One of the fields of most intensive and successful research is neurodegeneration and dementias, where many new phenotypes have been detected and classified using modern molecular genetics and animal and cellular models. Although the etiology and pathogenesis of Alzheimer disease and many other neurodegenerative and dementing disorders are still far from being elucidated, recent studies have provided important and meaningful results about the role of protein misfolding in neurodegeneration, eg, in the relationship of β-amyloid and tau protein in the pathogenesis of brain aging and Alzheimer disease, the role of α-synuclein and tau in neurodegeneration. Modern research has detected new forms of neurodegenerative disorders, such as the TDP-43-pathies, but has also provided new insights into the pathogenesis and molecular pathology of well-known entities, such as CAG repeat disorders, motor neuron diseases, prion diseases, peroxisomal and mitochondrial disorders. The present special issue will present various aspects of modern research in molecular neuropathology in order to provide new impacts for further research in this up-to-date field of neurosciences. Prof. Dr. Kurt A. Jellinger Guest Editor Submission All papers should be submitted to ijms@mdpi.org. To be published continuously until the deadline and papers will be listed together at the special issue website. Submitted papers should not have been published previously, nor be under consideration for publication elsewhere. All papers are refereed through a peer-review process. A guide for authors is available on the Instructions for Authors page. The International Journal of Molecular Sciences is an international peer-reviewed monthly journal published by Molecular Diversity Preservation International. Open Access publication fees are 800 CHF per paper. English correction fees and/or formatting fees (250 CHF) will be added in certain cases (1050 CHF per paper for those papers that require extensive additional formatting and/or English corrections). http://www.mdpi.com/1422-0067/10/6/2510/ The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions. http://www.mdpi.com/1422-0067/10/6/2510/ Wed, 03 Jun 2009 00:00:00 CEST International Journal of Molecular Sciences 2009-06-03 10 6 Review 2510 2557 1422-0067 Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders 2009-06-03 doi: 10.3390/ijms10062510 Yahya E. Choonara Viness Pillay Lisa C. du Toit Girish Modi Dinesh Naidoo Valence M.K. Ndesendo Sibongile R. Sibambo http://www.mdpi.com/1422-0067/10/4/1872/ Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ)-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer’s disease (AD) and Down’s syndrome. Moreover, Aβ-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Aβ domain of the amyloid precursor protein (APP) such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Aβ variants or an unaltered Aβ42/Aβ40 ratio favor vascular Aβ deposition over parenchymal plaques, but higher than critical levels of Aβ40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels. http://www.mdpi.com/1422-0067/10/4/1872/ Thu, 23 Apr 2009 00:00:00 CEST International Journal of Molecular Sciences 2009-04-23 10 4 Article 1872 1895 1422-0067 Hereditary and Sporadic Forms of Aβ-Cerebrovascular Amyloidosis and Relevant Transgenic Mouse Models 2009-04-23 doi: 10.3390/ijms10041872 Samir Kumar-Singh http://www.mdpi.com/1422-0067/10/3/1386/ Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as substantial optimism about successful therapeutic intervention. In 2009, we now have copious knowledge on the biochemical cascades that produce these proteins, the different modifications and forms in which these proteins exist, and the ability to selectively target these proteins for therapeutic intervention on an experimental basis. At the same time, there has been no discernible alteration in the natural course of AD in humans. While it may be that the complexity of AD will exceed our capacity to make significant treatment progress for decades or more, a paradigm shift from the reductionism that defines amyloid-β and tau hypotheses, to one that more accurately reflects the meaning of neuropathological changes, may be warranted. We and others have demonstrated that AD pathology is a manifestation of cellular adaptation, specifically as a defense against oxidative injury. As such, AD pathology is therefore a host response rather than a manifestation of cytotoxic protein injury, and is unlikely to be a fruitful target for therapeutic intervention. An “expansionist” view of the disease, we believe, with oxidative stress as a pleiotropic and upstream process, more aptly describes the relationship between various and numerous molecular alterations and clinical disease. http://www.mdpi.com/1422-0067/10/3/1386/ Thu, 26 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-26 10 3 Review 1386 1406 1422-0067 Molecular Pathogenesis of Alzheimer’s Disease: Reductionist versus Expansionist Approaches 2009-03-26 doi: 10.3390/ijms10031386 Rudy J. Castellani Xiongwei Zhu Hyoung-Gon Lee Mark A. Smith George Perry http://www.mdpi.com/1422-0067/10/3/1226/ Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer's disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn) has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target. http://www.mdpi.com/1422-0067/10/3/1226/ Tue, 17 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-17 10 3 Review 1226 1260 1422-0067 Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element 2009-03-17 doi: 10.3390/ijms10031226 David Olivares Xudong Huang Lars Branden Nigel H. Greig Jack T. Rogers http://www.mdpi.com/1422-0067/10/4/1609/ Structural variation in the human genome is likely to be an important mechanism for neuronal diversity and brain disease. A combination of multiple different forms of aneuploid cells due to loss or gain of whole chromosomes giving rise to cellular diversity at the genomic level have been described in neurons of the normal and diseased adult human brain. Here, we describe recent advances in molecular neuropathology based on the combination of slide-based cytometry with molecular biological techniques that will contribute to the understanding of genetic neuronal heterogeneity in the CNS and its potential impact on Alzheimer´s disease and age-related disorders. http://www.mdpi.com/1422-0067/10/4/1609/ Sun, 15 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-15 10 4 Review 1609 1627 1422-0067 Neuronal Aneuploidy in Health and Disease:A Cytomic Approach to Understand the Molecular Individuality of Neurons 2009-03-15 doi: 10.3390/ijms10041609 Thomas Arendt Birgit Mosch Markus Morawski http://www.mdpi.com/1422-0067/10/3/1045/ The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE). With the advent of more effective anti-retroviral therapies, HIVE has shifted from a sub-acute to a chronic condition. The neurodegenerative process in patients with HIVE is characterized by synaptic and dendritic damage to pyramidal neurons, loss of calbindin-immunoreactive interneurons and myelin loss. The mechanisms leading to neurodegeneration in HIVE might involve a variety of pathways, and several lines of investigation have found that interference with signaling factors mediating neuroprotection might play an important role. These signaling pathways include, among others, the GSK3b, CDK5, ERK, Pyk2, p38 and JNK cascades. Of these, GSK3b has been a primary focus of many previous studies showing that in infected patients, HIV proteins and neurotoxins secreted by immune-activated cells in the brain abnormally activate this pathway, which is otherwise regulated by growth factors such as FGF. Interestingly, modulation of the GSK3b signaling pathway by FGF1 or GSK3b inhibitors (lithium, valproic acid) is protective against HIV neurotoxicity, and several pilot clinical trials have demonstrated cognitive improvements in HIV patients treated with GSK3b inhibitors. In addition to the GSK3b pathway, the CDK5 pathway has recently been implicated as a mediator of neurotoxicity in HIV, and HIV proteins might activate this pathway and subsequently disrupt the diverse processes that CDK5 regulates, including synapse formation and plasticity and neurogenesis. Taken together, the GSK3b and CDK5 signaling pathways are important regulators of neurotoxicity in HIV, and modulation of these factors might have therapeutic potential in the treatment of patients suffering from HIVE. In this context, the subsequent sections will focus on reviewing the involvement of the GSK3b and CDK5 pathways in neurodegeneration in HIV. http://www.mdpi.com/1422-0067/10/3/1045/ Wed, 11 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-11 10 3 Review 1045 1063 1422-0067 Molecular Pathology of Neuro-AIDS (CNS-HIV) 2009-03-11 doi: 10.3390/ijms10031045 Leslie Crews Christina Patrick Cristian L. Achim Ian P. Everall Eliezer Masliah http://www.mdpi.com/1422-0067/10/3/1000/ Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The histopathological finding in SBMA is loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic AR. Heat shock proteins, ubiquitin-proteasome system and transcriptional regulation are also potential targets of therapy development for SBMA. http://www.mdpi.com/1422-0067/10/3/1000/ Tue, 10 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-10 10 3 Review 1000 1012 1422-0067 Neuropathology and Therapeutic Intervention in Spinal and Bulbar Muscular Atrophy 2009-03-10 doi: 10.3390/ijms10031000 Haruhiko Banno Masahisa Katsuno Keisuke Suzuki Fumiaki Tanaka Gen Sobue http://www.mdpi.com/1422-0067/10/3/976/ Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP) to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis. http://www.mdpi.com/1422-0067/10/3/976/ Mon, 09 Mar 2009 00:00:00 CET International Journal of Molecular Sciences 2009-03-09 10 3 Article 976 999 1422-0067 Molecular Pathology of Human Prion Diseases 2009-03-09 doi: 10.3390/ijms10030976 Gabor G. Kovacs Herbert Budka http://www.mdpi.com/1422-0067/10/3/724/ Lewy body diseases are characterized by the presence of Lewy bodies, alpha-synuclein(AS)-positive inclusions in the brain. Since their main component is conformationally modified AS, aggregation of the latter is thought to be a key pathogenic event in these diseases. The analysis of inclusion body constituents gives additional information about pathways also involved in the pathology of synucleinopathies. Widespread mitochondrial dysfunction is very closely related to disease development. The impairment of protein degradation pathways, including both the ubiquitin-proteasome system and the autophagy-lysosomepathway also play an important role during the development of Lewy body diseases. Finally, differential expression changes of isoforms corresponding to genes primarily involved in Lewy body formation point to alternative splicing as another important mechanism in the development of Parkinson’s disease, as well as dementia with Lewy bodies. The present paper attempts to give an overview of recent molecular findings related to the pathogenesis of Lewy body diseases. http://www.mdpi.com/1422-0067/10/3/724/ Thu, 26 Feb 2009 00:00:00 CET International Journal of Molecular Sciences 2009-02-26 10 3 Review 724 745 1422-0067 Molecular Pathology of Lewy Body Diseases 2009-02-26 doi: 10.3390/ijms10030724 Katrin Beyer Montserrat Domingo-Sàbat Aurelio Ariza http://www.mdpi.com/1422-0067/10/2/407/ Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches. http://www.mdpi.com/1422-0067/10/2/407/ Mon, 02 Feb 2009 00:00:00 CET International Journal of Molecular Sciences 2009-02-02 10 2 Review 407 440 1422-0067 Drosophila melanogaster as a Model Organism of Brain Diseases 2009-02-02 doi: 10.3390/ijms10020407 Astrid Jeibmann Werner Paulus http://www.mdpi.com/1422-0067/10/1/366/ New developments in molecular neuropathology have evoked increased demands for postmortem human brain tissue. The New South Wales Tissue Resource Centre (TRC) at The University of Sydney has grown from a small tissue collection into one of the leading international brain banking facilities, which operates with best practice and quality control protocols. The focus of this tissue collection is on schizophrenia and allied disorders, alcohol use disorders and controls. This review highlights changes in TRC operational procedures dictated by modern neuroscience, and provides examples of applications of modern molecular techniques to study the neuropathogenesis of many different brain disorders. http://www.mdpi.com/1422-0067/10/1/366/ Fri, 23 Jan 2009 00:00:00 CET International Journal of Molecular Sciences 2009-01-23 10 1 Review 366 384 1422-0067 The Importance of Brain Banks for Molecular Neuropathological Research: The New South Wales Tissue Resource Centre Experience 2009-01-23 doi: 10.3390/ijms10010366 Irina Dedova Antony Harding Donna Sheedy Therese Garrick Nina Sundqvist Clare Hunt Juliette Gillies Clive G. Harper http://www.mdpi.com/1422-0067/10/1/232/ The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS. http://www.mdpi.com/1422-0067/10/1/232/ Fri, 09 Jan 2009 00:00:00 CET International Journal of Molecular Sciences 2009-01-09 10 1 Review 232 246 1422-0067 Molecular Neuropathology of TDP-43 Proteinopathies 2009-01-09 doi: 10.3390/ijms10010232 Manuela Neumann http://www.mdpi.com/1422-0067/10/1/184/ Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies. http://www.mdpi.com/1422-0067/10/1/184/ Wed, 07 Jan 2009 00:00:00 CET International Journal of Molecular Sciences 2009-01-07 10 1 Review 184 212 1422-0067 Molecular Neuropathology of Gliomas 2009-01-07 doi: 10.3390/ijms10010184 Markus J. Riemenschneider Guido Reifenberger http://www.mdpi.com/1422-0067/9/11/2091/ A novel methodology named terminal continuation (TC) RNA amplification has been developed to amplify RNA from minute amounts of starting material. Utility of the TC RNA amplification method is demonstrated with two new modifications including obviating the need for second strand synthesis, and purifying the amplification template using column filtration prior to in vitro transcription (IVT). Using four low concentrations of RNA extracted from mouse brain (1, 10, 25 and 50 ng), one round TC RNA amplification was compared to one round amplified antisense RNA (aRNA) in conjunction with column filtration and drop dialysis purification. The TC RNA amplification without second strand synthesis performed extremely well on customdesigned cDNA array platforms, and column filtration was found to provide higher positive detection of individual clones when hybridization signal intensity was subtracted from corresponding negative control hybridization signal levels. Results indicate that TC RNA amplification without second strand synthesis, in conjunction with column filtration, is an excellent method for RNA amplification from extremely small amounts of input RNA from mouse brain and postmortem human brain, and is compatible with microaspiration strategies and subsequent microarray analysis. http://www.mdpi.com/1422-0067/9/11/2091/ Fri, 31 Oct 2008 00:00:00 CET International Journal of Molecular Sciences 2008-10-31 9 11 Article 2091 2104 1422-0067 Terminal Continuation (TC) RNA Amplification Enables Expression Profiling Using Minute RNA Input Obtained from Mouse Brain 2008-10-31 doi: 10.3390/ijms9112091 Melissa J. Alldred Shaoli Che Stephen D. Ginsberg