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Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
Fogli et al. used MALDI-TOF/MS to analyze CSF N-glycan profile and they suggest that this can be used to study leukodystrophies arising due to eIF2B mutations. They suggest that the method could also be extended to study other neurological disorders involving developmental gliogenesis/synaptogenesis abnormalities [56].
Protein and amino acids
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
As discussed, the translation process involved in MPS is driven by EAAs due to their ability to instigate the initiation of translation and the subsequent formation of nascent polypeptides. A study was performed to determine the mechanisms by which amino acids regulate translation initiation in skeletal muscle (73). A dose of amino acids with a ten-fold supra-physiological dose of leucine was compared to a physiological dose and with leucine removed for the effects on eukaryotic initiation factors (eIF) 2B and 4E. While both doses of amino acids increased MPS, the greater concentration of leucine had an even greater impact on MPS. In addition, the greater dose of leucine significantly increased the amount of eIF4E bound to eIF4G and the extent of phosphorylation of eIF4E was increased by 80% and 20%, respectively. However, removal of leucine decreased the rate of MPS by 40%. Furthermore, the inhibition of MPS was associated with a 40% decrease in eIF2B activity and an 80% fall in the abundance of eIF4E·eIF4G complex. The fall in eIF4G binding to eIF4E was associated with increased 4E-BP1 bound to eIF4E and a reduced phosphorylation of 4E-BP1 (73). These results suggest that the active eIF4E·eIF4G complex controls MPS when the amino acid concentration is above the physiological range; however, the absence of leucine reduces MPS through changes in both eIF2B and eIF4E binding.
Pathophysiology and Management of Shock
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The third, PERK (PKR-like ER kinase), is a serine/threonine kinase that, like IRE1, oligomerizes on release of its BiP anchor and autoactivates by transphosphorylation. Its substrate is the eukaryotic translation initiation factor 2a (eIF2a), which in its naked form binds eIF2B to exchange GDP for GTP to become active. Activated eIF2a can then load tRNA-Met on to the 40S ribosome to initiate protein translation. Phosphorylation of eIF2a on serine 51 prevents it from interacting with eIF2B, thus shutting down general protein translation. However, protected translation from ATF4 (activating transcription factor 4) is enhanced following phosphorylation of eIF2a, because of the presence of an alternative open reading frame 5’ upstream in the ATF4 mRNA. As with both XBP-1 and ATF6, ATF4 increases the production of molecular chaperones and antioxidant systems, as well as being important in gluconeogenesis (47).
Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver
Published in Nutritional Neuroscience, 2022
Lisanne E. Wisse, Denise Visser, Timo J. ter Braak, Abdellatif Bakkali, Eduard A. Struys, Christopher D. Morrison, Marjo S. van der Knaap, Truus E. M. Abbink
Vanishing white matter (VWM) is a chronic progressive neurological disease with rapid worsening of the disease provoked by stressors, especially febrile infections.1,2 Progression of the chronic disease is inversely correlated with the age of onset.3 VWM is caused by mutations in any of the five subunits of eIF2B with a reported genotype-phenotype correlation.3,4 eIF2B is essential for the protein synthesis and is a key factor of the integrated stress response (ISR).5 This ISR is activated by various types of proteotoxic stimuli, each activating a kinase that phosphorylates the α subunit of eIF2, e.g. protein kinase R (PKR) activated by viral infections, or general control non-derepressible 2 (GCN2) by shortage of amino acids.6 Phosphorylated eIF2 reduces eIF2B activity,5 which decreases general protein synthesis rates, yet increases the synthesis of specific proteins such as the transcription factor ATF4.7,8 These specific proteins induce a change in the transcription profile as a part of the ISR.6 Expression of this 'ISR transcriptome' is initially aimed to protect cells and restore proteostasis, but leads to cell death when the stress is long lasting or severe.
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
Vanishing white disease (VWD), as suggested by its name, is a disease that involves white matter in the central nervous system, where the nerves fibers are located. Any mutations in one of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) coding translation initiation factor eIF2B have been identified as the etiology of the disease. Astrocytes play an important role in white matter functioning, but fail to fully mature and express immature markers nestin and CD44 on their progenitor cells in VWD. The resulting effect is the lack of support for oligodendrocytes in transforming into myelin-producing cells in CNS [126,127]. The other proposed patho-mechanism of VMD is that the incompetent eIF2B fails to meet up the body’s needs under physiologic stress, which results in the consequent failure to restore microglia-astrocyte impairments [128]. The diagnosis can be made among patients with typical clinical features and MRI findings of VWD. Genetic testing is recommended but not necessary as 90% of diagnosed VWD patients show mutations in one of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) [126–128].
Design of novel PhMTNA inhibitors, targeting neurological disorder through homology modeling, molecular docking, and dynamics approaches
Published in Journal of Receptors and Signal Transduction, 2019
Prajisha Jayaprakash, Jayashree Biswal, Sureka Kanagarajan, Dhamodharan Prabhu, Prerana Gogoi, Shankar Prasad Kanaujia, Jeyaraman Jeyakanthan
VWM is characterized by progressive loss of brain white matter that affects the glial cells (Astrocytes and Oligodendrocytes), which comprises of the blood-brain barrier and form myelin sheaths to insulate neuronal axons. There are over hundred different eIF2B missense mutations in which any one of the ubiquitously expressed genes encoding the five subunits of eukaryotic translation initiation that have been associated with the varying levels of disorder. Eukaryotic Translation Initiation Factor 2B (eIF2B) [2] plays an essential role during the initiation and regulation of protein biosynthesis. During protein synthesis, eIF2 bound to a GTP molecule (eIF2•GTP) assists in the delivery of the initiator tRNA (Met-tRNAiMet) to the small (30S) ribosomal subunit [3]. Upon delivery, the active eIF2•GTP gets converted to inactive eIF2•GDP and thus, has to be converted back to its active form for the consecutive rounds of translation initiation to occur [4]. This reactivation is carried out by the heterodecameric Guanine Nucleotide Exchange factor (GEF). Under stress conditions, eIF2B regulates the process of protein biosynthesis by rate limiting the translation initiation [5]. It has been reported that mutations in any of the eIF2B subunits lead to severe autosomal recessive neurodegenerative disorder which is termed as leukoencephalopathy with VWM [6].