Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three putative resistant (R1, R2, R3) and one susceptible (S) Lolium rigidum populations originating from Greece were studied for resistance to ALS and ACCase inhibiting herbicides, using whole plant, sequencing of als and accase gene, and in vitro ALS activity assays. The S and two R (R1, R2) populations were also evaluated for fitness in competition with wheat. The whole plant assay indicated unsatisfactory control of the R populations with mesosulfuron-methyl + iodosulfuron-methyl or pinoxaden application, whereas sequencing of the als gene revealed that all ALS-resistant individuals had a Pro-197 substitution by Leu, Glu, Ser, Ala, Thr, or Gln. In addition, the accase gene of all pinoxaden resistant individuals had an Ile-2041 substitution by Asn or Thr. Furthermore, sequencing of the individuals surviving mesosulfuron-methyl + iodosulfuron-methyl or pinoxaden treatment revealed co-existence of point mutations in the accase or als genes, respectively, demonstrating multiple resistance. The in vitro activity of the ALS enzyme confirmed that resistance to mesosulfuron-methyl + iodosulfuron-methyl was due altered target-site. The recorded higher vigor and greater competitive ability of S population against wheat as compared with that of the R populations suggests an associated fitness cost with multiple resistance.
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PMID:Mechanisms of Lolium rigidum multiple resistance to ALS- and ACCase-inhibiting herbicides and their impact on plant fitness. 3228 38

The activated mammalian Ste20-like serine/threonine kinases 1 (MST1) was found in the central nervous system diseases, such as cerebral ischemia, stroke and ALS, which were related with cognitions. The aim of this study was to examine the effect of elevated MST1 on memory functions in C57BL/6J mice. We also explored the underlying mechanism about the pattern alteration of neural oscillations, closely associated with cognitive dysfunctions, at different physiological rhythms, which were related to a wide range of basic and higher-level cognitive activities. A mouse model of the adeno-associated virus (AAV)-mediated overexpression of MST1 was established. The behavioral experiments showed that spatial memory was significantly damaged in MST1 mice. The distribution of either theta or gamma power was clearly disturbed in MST1 animals. Moreover, the synchronization in both theta and gamma rhythms, and theta-gamma cross-frequency coupling were significantly weakened in MST1 mice. In addition, the expressions of GABAA receptor, GAD67 and parvalbumin (PV) were obviously increased in MST1 mice. Meanwhile, blocking MST1 activity could inhibit the activation of FOXO3a and YAP. The above data suggest that MST1-overexpression may induce memory impairments via disturbing the patterns of neural activities, which is possibly associated with the abnormal GABAergic expression level.
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PMID:Over-expressed MST1 impaired spatial memory via disturbing neural oscillation patterns in mice. 3246 68

Endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, and mitochondrial dynamics. However, the molecular organization, functions, regulation of ERMCS, and the physiological roles of altered ERMCSs are not fully understood in higher eukaryotes. We found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga-mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.
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PMID:Miga-mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis. 3264 43

The taxonomically challenging genus Amaranthus (Family Amaranthaceae) includes important agricultural weed species that are being spread globally as grain contaminants. We hypothesized that the ALS gene will help resolve these taxonomic challenges and identify potentially harmful resistant biotypes. We obtained 153 samples representing 26 species from three Amaranthus subgenera and included in that incorporated ITS, ALS (domains C, A and D) and ALS (domains B and E) sequences. Subgen. Albersia was well supported, but subgen. Amaranthus and subgen. Acnida were not. Amaranthus tuberculatus, A. palmeri and A. spinosus all showed different genetic structuring. Unique SNPs in ALS offered reliable diagnostics for most of the sampled Amaranthus species. Resistant ALS alleles were detected in sixteen A. tuberculatus samples (55.2%), eight A. palmeri (27.6%) and one A. arenicola (100%). These involved Ala122Asn, Pro197Ser/Thr/Ile, Trp574Leu, and Ser653Thr/Asn/Lys substitutions, with Ala122Asn, Pro197Thr/Ile and Ser653Lys being reported in Amaranthus for the first time. Moreover, different resistant mutations were present in different A. tuberculatus populations. In conclusion, the ALS gene is important for species identification, investigating population genetic diversity and understanding resistant evolution within the genus Amaranthus.
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PMID:Species identification, phylogenetic analysis and detection of herbicide-resistant biotypes of Amaranthus based on ALS and ITS. 3267 46

Descurainia sophia L. is one of the most notorious broadleaf weeds in winter wheat fields of China. In this study, 95 out of 163 (58.3%) D. sophia populations which were collected from provinces of Hebei, Shandong, Henan, Shanxi, Shaanxi and Jiangsu, have evolved resistance to tribenuron-methyl. The als1 and als2 were cloned in all test D. sophia populations, while als3 and als4 were identified only in some of the populations. Resistant mutations of Pro-197-Ser/Thr/Leu/His/Ala/Arg, Asp-376-Glu and Trp-574-Leu were identified in tribenuron-methyl-resistant (TR) D. sophia plants, while the Pro-197-Arg was first identified in D. sophia in this study. These resistant mutations displayed no preference between ALS1 and ALS2. However, Pro-197-Ser/Thr and Trp-574-Leu were identified in all ALS isozymes, while the other mutations were not. In addition, some resistant mutations displayed regional differences, the frequency of Pro-197-Ser in Shandong and Trp-574-Leu in Shanxi province is much higher than that in other provinces.
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PMID:Investigation of resistant level to tribenuron-methyl, diversity and regional difference of the resistant mutations on acetolactate synthase (ALS) isozymes in Descurainia sophia L. from China. 3282 71

Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing-like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.
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PMID:Quality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD. 3295 50

The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Notably, Pin1 is widely expressed in the central and peripheral nervous system, where it regulates a variety of neuronal processes, including neuronal development, apoptosis, and synaptic activity. However, despite studies reporting the interaction of Pin1 with neuronal substrates or its involvement in specific signaling pathways, a more comprehensive understanding of its biological functions at neuronal level is still lacking. Besides its implication in physiological processes, a growing body of evidence suggests the crucial involvement of Pin1 in aging and age-related and neurodegenerative diseases, including Alzheimer's disease, Parkinson disease, frontotemporal dementias, Huntington disease, and amyotrophic lateral sclerosis, where it mediates profoundly different effects, ranging from neuroprotective to neurotoxic. Therefore, a more detailed understanding of Pin1 neuronal functions may provide relevant information on the consequences of Pin1 deregulation in age-related and neurodegenerative disorders.
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PMID:The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration. 3308 64


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