Nol9 Is a Spatial Regulator for the Human ITS2 Pre-rRNA Endonuclease–Kinase Complex

Publication date: Available online 6 July 2019Source: Journal of Molecular BiologyAuthor(s): Jacob Gordon, Monica C. Pillon, Robin E. StanleyAbstractThe ribosome plays a universal role in translating the cellular proteome. Defects in the ribosome assembly factor Las1L are associated with congenital lethal motor neuron disease and X-linked intellectual disability disorders, yet its role in processing precursor ribosomal RNA (pre-rRNA) is largely unclear. The Las1L endoribonuclease associates with the Nol9 polynucleotide kinase to form the internal transcribed spacer 2 (ITS2) pre-rRNA endonuclease–kinase machinery. Together, Las1L–Nol9 catalyzes RNA cleavage and phosphorylation to mark the ITS2 for degradation. While ITS2 processing is critical for the production of functional ribosomes, the regulation of mammalian Las1L–Nol9 remains obscure. Here we characterize the human Las1L–Nol9 complex and identify critical molecular features that regulate its assembly and spatial organization. We establish that Las1L and Nol9 form a higher-order complex and identify the regions responsible for orchestrating this intricate architecture. Structural analysis by high-resolution imaging defines the intricate spatial pattern of Las1L–Nol9 within the nucleolar sub-structure linked with late pre-rRNA processing events. Furthermore, we uncover a Nol9-encoded nucleolar localization sequence that is responsible for nucleolar transport of the assembled Las1L–Nol9 ...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research

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Publication date: Available online 6 July 2019Source: Journal of Molecular BiologyAuthor(s): Jacob Gordon, Monica C. Pillon, Robin E. StanleyAbstractThe ribosome plays a universal role in translating the cellular proteome. Defects in the ribosome assembly factor Las1L are associated with congenital lethal motor neuron disease and X-linked intellectual disability disorders, yet its role in processing precursor ribosomal RNA (pre-rRNA) is largely unclear. The Las1L endoribonuclease associates with the Nol9 polynucleotide kinase to form the internal transcribed spacer 2 (ITS2) pre-rRNA endonuclease-kinase machinery. Together,...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research
Conclusion: This study provides a unique contribution in advancing our understanding of dysphagia in Motor Neurone Disease. Professionals need to view dysphagia within the disease as a whole, and recognize personal values, preferences and coping strategies of people with Motor Neurone Disease, in the management of dysphagia. IMPLICATIONS FOR REHABILITATION Recognizing the experiences of dysphagia in Motor Neurone Disease contributes to provision of patient-centred care. Professional services for dysphagia should consider the overall experience of living with Motor Neurone Disease rather than focusing on dysphagia alone. So...
Source: Disability and Rehabilitation - Category: Rehabilitation Authors: Tags: Disabil Rehabil Source Type: research
(Natural News) A newly developed oral spray could further improve the effects of anti-spasticity treatments on the symptoms of muscle stiffness. Called “naximols,” the medicine employed delta-9 tetrahydrocannabinol THC and cannabidiol, two natural compounds derived from cannabis (Cannabis sativa). Muscle spasticity often causes disability and lower quality of life in patients with motor neuron disease. The...
Source: NaturalNews.com - Category: Consumer Health News Source Type: news
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
Conclusion The key problem with the ND field is the lack of understanding in the events preceding the development of protein-based markers – such as Tau – currently used to diagnose NDs. By this stage, the diseases become more difficult to treat. SncRNAs play an important regulatory role in the maintenance of the homeostatic brain. Therefore, changes in their concentration levels can be indicative of mechanistic changes that could precede protein-based markers. One single sncRNA biomarker is unlikely to differentiate between diseases. However, a combination of sncRNA biomarkers could be illustrative of the me...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
CONCLUSIONS: Pain in motor neuron disease seems to have certain and multiple characteristics, which is why there is a need to develop and implement pain assessment methods adapted to this population. Such methods may help make pain more predictable, and increase the possibilities to provide effective and individually tailored pain treatment. IMPLICATIONS FOR REHABILITATION Pain is a common, but often neglected, ailment in motor neuro disease, which deserves more attention from health care. Staff should provide information about the pain being possible to treat successfully with medication, by contrast to the possibility of...
Source: Disability and Rehabilitation - Category: Rehabilitation Authors: Tags: Disabil Rehabil Source Type: research
Conclusions The momentous advances in spinal imaging in ALS suggest the spinal metrics may soon be used as validated diagnostic, monitoring, and prognostic markers, contributing both to individualized patient care and pharmacological trials. Author Contributions ME, GQ, PB, and P-FP contributed equally to the conceptualization, drafting, and revision of the manuscript. Funding Peter Bede is supported by the Health Research Board (HRB—Ireland; HRB EIA-2017-019), the Iris O'Brien Foundation, the Irish Institute of Clinical Neuroscience IICN—Novartis Ireland Research Grant, and the Research Motor Neur...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Discussion: Our results demonstrated that cancer risk was not increased in our MS population; but age and sex different distribution may partly drive cancer risk. Higher cancer risk in MS patients switching more than two DMTs should take into account in treatment decision making. Introduction Multiple Sclerosis (MS) is a severe acquired autoimmune neurodegenerative disease of the central nervous system (CNS) with extremely variable disease course, that usually affects persons in their third/four decades of life, even if late onset is described (1). Women had a prevalence/incidence rate approximately double than men (...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
The objectives of our study were to determine the sensitivity and specificity of anti-NT5c1A for sIBM, demonstrate demographic, clinical and serological predictors for anti-NT5c1A positivity and determine if anti-nuclear antibody (ANA) indirect immunofluorescence (IIF) staining on HEp-2 cells is a reliable screening method for anti-NT5c1A. Methods: Sera from sIBM patients and controls were stored at −80°C until required for analysis. IgG antibodies to NT5c1A were detected by an addressable laser bead immunoassay (ALBIA) using a full-length human recombinant protein. Autoantibodies to other autoimmune myopathy an...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Abstract Mutations in the HADHB gene induce dysfunctions in the beta-oxidation of fatty acids and result in a MTP deficiency, which is characterized by clinical heterogeneity, such as cardiomyopathy and recurrent Leigh-like encephalopathy. In contrast, milder forms of HADHB mutations cause the later onset of progressive axonal peripheral neuropathy (approximately 50-80%) and myopathy with or without episodic myoglobinuria. The mechanisms linking neuronal defects in these diseases to the loss of HADHB function currently remain unclear. Drosophila has the CG4581 (dHADHB) gene as a single human HADHB homologue. We he...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research
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