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61.
Alexandra M. Nicholson NiCole A. Finch Aleksandra Wojtas Matt C. Baker Ralph B. Perkerson III Monica Castanedes‐Casey Linda Rousseau Luisa Benussi Giuliano Binetti Roberta Ghidoni Ging‐Yuek R. Hsiung Ian R. Mackenzie Elizabeth Finger Bradley F. Boeve Nilüfer Ertekin‐Taner Neill R. Graff‐Radford Dennis W. Dickson Rosa Rademakers 《Journal of neurochemistry》2013,126(6):781-791
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk.
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Jeffrey G. Marblestone Samir Butt Devin M. McKelvey David E. Sterner Michael R. Mattern Benjamin Nicholson Michael J. Eddins 《Cell biochemistry and biophysics》2013,67(1):161-167
The ubiquitin pathway regulates diverse functions including protein localization and stability. The complexity of the pathway involving nearly 40 identified E2 conjugating enzymes and over 600 E3 ligases raises the issue of specificity. With the E2s and E3s fitting into a limited number of classes based on bioinformatics, structures, and proven activities, there is not a clear picture as to what would determine which E2/E3 enzyme pair would be functional. There have been many reports of limited E2/E3 activity profiling with a small number of E2s and E3s. We have expanded on this to investigate the activity of ubiquitin E2s covering the majority of the reported classes/families in concert with a number of E3s implicated in a variety of diseases. Using an ELISA-based assay we screened 10 E3 ligases against a panel of 11 E2s to determine which E2/E3 pairs exhibited E3 autoubiquitylation activity. In addition, the ubiquitin chain linkage preference by certain E2/E3 pairs was investigated. Finally, substrate ubiquitylation was assayed for the E3 ligase MuRF1 using various E2/MuRF1 pairs. These studies demonstrate the utility of identifying the correct E2/E3 pair to monitor specific substrate ubiquitylation. 相似文献
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Oliver A.H. Jones Lee A. Walker Jeremy K. Nicholson Richard F. Shore Julian L. Griffin 《Comparative biochemistry and physiology. Part D, Genomics & proteomics》2007,2(4):316-321
Proton (1H) Nuclear Magnetic Resonance (NMR) spectroscopy was used to investigate the biochemical response of bank voles and wood mice (two wild rodent species frequently found on metal-contaminated sites) to chronic cadmium (Cd) insult. Similar effects, in terms of both metabolic changes (consistent with cellular acidosis) and induced metallothionin (MT) production were observed in all animals. These changes appeared to be an adaptation of the liver to toxic insult rather than onset of a toxic effect, and, in common with previous studies, were more marked in bank voles than wood mice. This may have reflected the greater Cd intake and assimilation of the former but was not explained by differences in concentrations of free (non MT-bound) Cd; concentrations of which were negligible in both voles and mice. Responses to Cd insult were detected in both species even though their bodies contained cadmium concentrations well below the World Health Organisation critical renal concentration of 200 μg/g dry mass. 相似文献
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T. F. Nicholson 《CMAJ》1929,21(5):563-566
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