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Advances in Neurobiology

Erik M Lehmkuhl, Daniela C Zarnescu
Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease...
2018: Advances in Neurobiology
Craig L Bennett, Albert R La Spada
Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4...
2018: Advances in Neurobiology
Marc Shenouda, Ashley B Zhang, Anna Weichert, Janice Robertson
The discovery of TDP-43 as a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was first made in 2006. Prior to 2006 there were only 11 publications related to TDP-43, now there are over 2000, indicating the importance of TDP-43 to unraveling the complex molecular mechanisms that underpin the pathogenesis of ALS/FTLD. Subsequent to this discovery, TDP-43 pathology was also found in other neurodegenerative diseases, including Alzheimer's disease, the significance of which is still in the early stages of exploration...
2018: Advances in Neurobiology
Chaitali Misra, Feikai Lin, Auinash Kalsotra
RNA metabolism impacts different steps of mRNA life cycle including splicing, polyadenylation, nucleo-cytoplasmic export, translation, and decay. Growing evidence indicates that defects in any of these steps lead to devastating diseases in humans. This chapter reviews the various RNA metabolic mechanisms that are disrupted in Myotonic Dystrophy-a trinucleotide repeat expansion disease-due to dysregulation of RNA-Binding Proteins. We also compare Myotonic Dystrophy to other microsatellite expansion disorders and describe how some of these mechanisms commonly exert direct versus indirect effects toward disease pathologies...
2018: Advances in Neurobiology
Nikita Fernandes, Nichole Eshleman, J Ross Buchan
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by cytoplasmic protein aggregates within motor neurons. These aggregates are linked to ALS pathogenesis. Recent evidence has suggested that stress granules may aid the formation of ALS protein aggregates. Here, we summarize current understanding of stress granules, focusing on assembly and clearance. We also assess the evidence linking alterations in stress granule formation and dynamics to ALS protein aggregates and disease pathology...
2018: Advances in Neurobiology
Phillip L Price, Dmytro Morderer, Wilfried Rossoll
Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations/deletions within the survival of motor neuron 1 (SMN1) gene that lead to a pathological reduction of SMN protein levels. SMN is part of a multiprotein complex, functioning as a molecular chaperone that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNP). In addition to its role in spliceosome formation, SMN has also been found to interact with mRNA-binding proteins (mRBPs), and facilitate their assembly into mRNP transport granules...
2018: Advances in Neurobiology
Kaitlin Weskamp, Sami J Barmada
Ribonucleic acid (RNA) homeostasis is dynamically modulated in response to changing physiological conditions. Tight regulation of RNA abundance through both transcription and degradation determines the amount, timing, and location of protein translation. This balance is of particular importance in neurons, which are among the most metabolically active and morphologically complex cells in the body. As a result, any disruptions in RNA degradation can have dramatic consequences for neuronal health. In this chapter, we will first discuss mechanisms of RNA stabilization and decay...
2018: Advances in Neurobiology
Ashley Boehringer, Robert Bowser
In eukaryotic cells, transcription and translation are compartmentalized by the nuclear membrane, requiring an active transport of RNA from the nucleus into the cytoplasm. This is accomplished by a variety of transport complexes that contain either a member of the exportin family of proteins and translocation fueled by GTP hydrolysis or in the case of mRNA by complexes containing the export protein NXF1. Recent evidence indicates that RNA transport is altered in a number of different neurodegenerative diseases including Huntington's disease, Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis...
2018: Advances in Neurobiology
Ileana Lorenzini, Stephen Moore, Rita Sattler
The molecular process of RNA editing allows changes in RNA transcripts that increase genomic diversity. These highly conserved RNA editing events are catalyzed by a group of enzymes known as adenosine deaminases acting on double-stranded RNA (ADARs). ADARs are necessary for normal development, they bind to over thousands of genes, impact millions of editing sites, and target critical components of the central nervous system (CNS) such as glutamate receptors, serotonin receptors, and potassium channels. Dysfunctional ADARs are known to cause alterations in CNS protein products and therefore play a role in chronic or acute neurodegenerative and psychiatric diseases as well as CNS cancer...
2018: Advances in Neurobiology
Ravindra N Singh, Natalia N Singh
Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7...
2018: Advances in Neurobiology
Mark T W Ebbert, Rebecca J Lank, Veronique V Belzil
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic...
2018: Advances in Neurobiology
Yousheng Wang, Hengming Ke
This chapter describes crystal structures of phosphodiesterases (PDEs) that are involved in CNS diseases and their interactions with family selective inhibitors. The structural comparison identifies a small hydrophobic pocket next to the active site, which may be valuable for improvement of selectivity of PDE inhibitors.
2017: Advances in Neurobiology
Anjana Munshi, Satrupa Das
Phosphodiesterase (PDE) gene family is a large family having at least 21 genes and multiple versions (isoforms) of the phosphodiesterase enzymes. These enzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and therefore, play a pivotal role in various cellular functions. PDE inhibitors (PDEI) are drugs that block one or more of the five subtypes of the PDE family and thereby prevent inactivation of the intracellular cAMP and cGMP by the respective PDE-subtypes...
2017: Advances in Neurobiology
Rui-Ting Wen, Jian-Hui Liang, Han-Ting Zhang
Substance dependence is a chronic relapsing brain disorder associated with adaptational changes in synaptic plasticity and neuronal functions. The high levels of substance consumption and relapse rate suggest more reliable medications are in need to better address the underlying causes of this disease. It has been well established that the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) and their signaling systems play an important role in the molecular mechanisms of substance taking behaviors...
2017: Advances in Neurobiology
Gretchen L Snyder, Kimberly E Vanover
Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in patients with schizophrenia and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of this serious mental disorder...
2017: Advances in Neurobiology
Lawrence P Wennogle, Helen Hoxie, Youyi Peng, Joseph P Hendrick
The focus of this chapter is on the cyclic nucleotide phosphodiesterase 1 (PDE1) family. PDE1 is one member of the 11 PDE families (PDE 1-11). It is the only phosphodiesterase family that is calcium/calmodulin activated. As a result, whereas other families of PDEs 2-11 play a dominant role controlling basal levels of cyclic nucleotides, PDE1 is involved when intra-cellular calcium levels are elevated and, thus, has an "on demand" or activity-dependent involvement in the control of cyclic nucleotides in excitatory cells including neurons, cardiomyocytes and smooth muscle...
2017: Advances in Neurobiology
Chong Zhang, Lindsay M Lueptow, Han-Ting Zhang, James M O'Donnell, Ying Xu
Cyclic nucleotide PDEs are a super-family of enzymes responsible for regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Through their catalysis, PDEs are able to exert tight regulation over these important intracellular signaling cascades. Previously, PDEs have been implicated in learning and memory, as well as in mood disorders, such as anxiety and depression. PDE2 is of special interest due to its high level of expression in the forebrain, specifically in the isocortex, entorhinal cortex, striatum, hippocampus, amygdala, and medial habenula...
2017: Advances in Neurobiology
Francesca R Fusco, Emanuela Paldino
Huntington's disease (HD) is an autosomal-dominant rare inherited neurodegenerative disease characterized by a wide variety of symptoms encompassing movement, cognition and behaviour. The cause of the disease is a genetic mutation in the huntingtin protein. The mutation leads to an unstable CAG expansion, translated into a polyglutamine domain within the disease protein. Indeed, huntingtin has a CAG/polyglutamine expansion in the range of 6-39 units in normal individuals, whereas it reaches 39-180 units in HD patients...
2017: Advances in Neurobiology
Fernando E Padovan-Neto, Anthony R West
Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of cyclic nucleotides (cAMP/cGMP) in the brain. Several classes of PDE enzymes with distinct tissue distributions, cyclic nucleotide selectivity, and regulatory factors are highly expressed in brain regions subserving cognitive and motor processes known to be disrupted in neurodegenerative diseases such as Parkinson's disease (PD). Furthermore, small-molecule inhibitors of several different PDE family members alter cyclic nucleotide levels and favorably enhance motor performance and cognition in animal disease models...
2017: Advances in Neurobiology
C Dorner-Ciossek, K S Kroker, H Rosenbrock
Inhibition of phosphodiesterases (PDEs) has been demonstrated to enhance performance of animals in various cognition tasks and accordingly PDE inhibitors have been proposed as new approach for treatment of cognitive dysfunction (Reneerkens et al. Psychopharmacology 202:419-443, 2009; Schmidt Curr Top Med Chem 10(2):222-230, 2010). One of the eleven PDE isoforms, showing expression in cognition relevant brain regions across species, is PDE9, which hydrolyzes cGMP only. Furthermore, it is well established that the nitric oxide (NO)/cGMP pathway and NMDA receptor signaling has a crucial function in synaptic plasticity and cognitive function...
2017: Advances in Neurobiology
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