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Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans.
Cell Mol Life Sci 2008 Apr
PMID:Molecular mimicry in neurological disease: what is the evidence? 1819 92

Mitochondrial dysfunction has been increasingly shown as a critical process that makes certain areas of the brain more susceptible not only to neurological disease but also to aging. Quantitative histochemistry is a series of procedures for measuring select metabolites in discrete regions of the brain, as they exist in vivo. The development of this method has been useful in establishing energy imbalance following ischemia but more recently has become useful in studying those processes related to the mitochondria which make the brain more susceptible to a variety of neurological insults. The relatively inexpensive cost to assay a given brain metabolite makes this methodology useful in the interpretation of molecular and biochemical responses in terms of the condition of the tissue following a neurological insult.
Methods Mol Biol 2007
PMID:Biochemical methods to assess the coupling of brain energy metabolism in control and disease states. 1830 27

A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biology. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1-7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer's disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.
J Mol Med (Berl) 2008 Jun
PMID:Brain renin angiotensin in disease. 1838 68

Multiple sclerosis (MS) is a progressive neurological disease caused by an autoimmune attack to the central nervous system (CNS). MS is thought to result from a complex interaction between genetic and environmental factors. In this review we analyze the contribution of genomics, trancriptomics and proteomics in delineating these factors, as well as their utility for the monitoring of disease progression, the identification of new targets for therapeutic intervention and the early detection of individuals at risk.
J Cell Mol Med 2008 Aug
PMID:Systems biology approaches for the study of multiple sclerosis. 1841 93

The aim of this study is to determine if there is a pathology-related variation in mitochondrial (mt)DNA copy numbers in brains of patients with multiple sclerosis (MS). Our recent study demonstrated an age-dependent but excluded a MS pathology-related increase in the proportion of cytochrome oxidase (COX)-negative cells and deleted mtDNA molecules in postmortem brain tissue specimens of patients and controls (Blokhin et al., Neuromolecular Medicine, in press, 2008). This corollary study further extends our efforts defining mitochondrial contributions to tissue degeneration associated with inflammatory demyelination. Copy number variations of mtDNA molecules were defined by quantifying the mtDNA ND1 gene copies relative to the invariable nuclear ribosomal 18S gene copies (ND1/r18S) using real-time polymerase chain reaction analyses in laser dissected, COX-positive and COX-negative single neurons and glial cells from frozen postmortem normal-appearing gray (NAGM) and white matter (NAWM) regions and chronic active plaques of MS patients, and gray matter (GM) and white matter (WM) regions of age matched non-neurological disease (NND) controls. ND1/r18S values were correlated with tissue regions, pathology, and age. While the ND1/r18S values were similar in NAWM and plaque-containing specimens of MS patients as well as in NAWM of patients and WM of age-matched NND controls, we found significantly higher mtDNA copy number values in neurons of NAGM than in cells of other MS brain regions. The ND1/r18S values were even higher in NAGM than in GM of age-matched NND controls. An age-related decline in ND1/r18S values was also noted in neurons of both MS patients and NND controls. These observations exclude a change in mtDNA copy numbers in plaques, however, suggest a compensatory replication of mtDNA or mitochondria in the cortex with neuroaxonal loss in MS. The age-related decline in mtDNA copy numbers may explain some features of late-onset MS.
J Mol Neurosci 2008 Jul
PMID:Variations in mitochondrial DNA copy numbers in MS brains. 1856 18

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.
Hum Mol Genet 2008 Dec 01
PMID:Identification of Arx transcriptional targets in the developing basal forebrain. 1879 76

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.
Int J Mol Sci 2009 Feb
PMID:Drosophila melanogaster as a model organism of brain diseases. 1933 15

The microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes play central roles in neurodegenerative disorders. Mutations in each gene cause familial disease, whereas common genetic variation at both loci contributes to susceptibility to sporadic neurodegenerative disease. Here, we demonstrate exquisite gene regulation of the human MAPT and SNCA transgene loci and functional complementation in neuronal cell cultures and organotypic brain slices using the herpes simplex virus type 1 (HSV-1) amplicon-based infectious bacterial artificial chromosome (iBAC) vector to express complete loci >100 kb. Cell cultures transduced by iBAC vectors carrying a 143 kb MAPT or 135 kb SNCA locus expressed the human loci similar to the endogenous gene. We focused on analysis of the iBAC-MAPT vector carrying the complete MAPT locus. On transduction into neuronal cultures, multiple MAPT transcripts were expressed from iBAC-MAPT under strict developmental and cell type-specific control. In primary neurons from Mapt(-/-) mice, the iBAC-MAPT vector expressed the human tau protein, as detected by enzyme-linked immunosorbent assay and immunocytochemistry, and restored sensitivity of Mapt(-/-) neurons to Abeta peptide treatment in dissociated neuronal cultures and in organotypic slice cultures. The faithful retention of gene expression and phenotype complementation by the system provides a novel method to analyze neurological disease genes.
Mol Ther 2009 Sep
PMID:Physiological transgene regulation and functional complementation of a neurological disease gene deficiency in neurons. 1935 23

The characteristic CNS responses to injury including increased cell production and attempts at regenerative repair - implicitly predicted where not directly demonstrated by Cajal, but only now more fully confirmed - have important implications for regenerative therapies. Spontaneous CNS cell replacement compares poorly with the regenerative functional repair seen elsewhere, but harnessing, stimulating or supplementing this process represents a new and attractive therapeutic concept.Stem cells, traditionally defined as clone-forming, self-renewing, pluripotent progenitor cells, have already proved themselves to be an invaluable source of transplantation material in several clinical settings, most notably haematological malignancy, and attention is now turning to a wider variety of diseases in which there may be potential for therapeutic intervention with stem cell transplantation. Neurological diseases, with their reputation for relentless progression and incurability are particularly tantalising targets. The optimal source of stem cells remains to be determined but bone marrow stem cells may themselves be included amongst the contenders.Any development of therapies using stem cells must depend on an underlying knowledge of their basic biology. The haemopoietic system has long been known to maintain circulating populations of cells with short life spans, and this system has greatly informed our knowledge of stem cell biology. In particular, it has helped yield the traditional stem cell model - a hierarchical paradigm of progressive lineage restriction. As cells differentiate, their fate choices become progressively more limited, and their capacity for proliferation reduced, until fully differentiated, mitotically quiescent cells are generated. Even this, however, is now under challenge.
Methods Mol Biol 2009
PMID:Adult stem cells for the treatment of neurological disease. 1937 93

According to a widely supported but unproven concept, the autoimmune mechanisms that drive neuroinflammation in multiple sclerosis (MS) are triggered by virus infection. However, a direct viral trigger of MS has not been identified. MS models in non-human primates suggest that lifelong asymptomatic infection with certain herpesviruses (e.g. cytomegalovirus) creates a repertoire of potentially autoreactive memory T cells. When these are exposed to antigens released after central nervous system injury as a consequence of an unknown pathogenic event, they are reactivated and induce autoimmune neurological disease. This response-to-damage of antiviral memory cells can take place years after the initiating infection. Consequently, elucidating the anti-herpesvirus T-cell repertoire might provide new targets for preventive diagnosis and therapy.
Trends Mol Med 2009 Jun
PMID:Multiple sclerosis - a response-to-damage model. 1945 Oct 35


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