Abstract:
: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. We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Nicholson AM,Finch NA,Wojtas A,Baker MC,Perkerson RB 3rd,Castanedes-Casey M,Rousseau L,Benussi L,Binetti G,Ghidoni R,Hsiung GY,Mackenzie IR,Finger E,Boeve BF,Ertekin-Taner N,Graff-Radford NR,Dickson DW,Rademakers Rdoi
10.1111/jnc.12329subject
Has Abstractpub_date
2013-09-01 00:00:00pages
781-91issue
6eissn
0022-3042issn
1471-4159journal_volume
126pub_type
杂志文章abstract::Abstract The dualistic activities of the amyloid beta (Abeta) peptide as a pro-oxidant and ubiquitous constituent of amyloid deposits in Alzheimer's disease plaques and as an antioxidant of purported physiological function has been suggested but the mechanisms are far from being understood. In this report we measure s...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2004.02778.x
更新日期:2004-11-01 00:00:00
abstract::S-100 proteins are a group of three 21-kilodalton, acidic, Ca2+-binding proteins of the "E-F hand" type shown to regulate several cell activities, including microtubule (MT) assembly-disassembly. We show here that S-100 proteins interact with MTs assembled from either whole microtubule protein or purified tubulin, bot...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb01841.x
更新日期:1989-04-01 00:00:00
abstract::The RNA integrity number (RIN) is often considered to be a critical measure of the quality of postmortem human brains. However, it has been suggested that RINs do not necessarily reflect the availability of intact mRNA. Using the Agilent bioanalyzer and qRT-PCR, we explored whether RINs provide a meaningful way of ass...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13637
更新日期:2016-07-01 00:00:00
abstract::CYP46A1 is a neuron-specific cytochrome P450 that plays a pivotal role in maintaining cholesterol homeostasis in the CNS. However, the molecular mechanisms underlying human CYP46A1 expression are still poorly understood, partly because of the lack of a cellular model that expresses high levels of CYP46A1. Our previous...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2011.07577.x
更新日期:2012-01-01 00:00:00
abstract::L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lackin...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04655.x
更新日期:2007-08-01 00:00:00
abstract::Parkinson's disease is a common neurodegenerative disorder with a mainly sporadic aetiology, although a number of monogenic familiar forms are known. Most of the motor symptoms are due to selective depletion of dopaminergic, neuromelanin-containing neurones of the substantia nigra pars compacta. Neuromelanin is the da...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1111/j.1471-4159.2005.03638.x
更新日期:2006-02-01 00:00:00
abstract::In this article, we demonstrate that an increase in intracellular Ca2+ concentration may represent a specific common step(s) in the mechanism(s) of action of glutamate (Glu) and depolarizing agents on formation of inositol phosphates (IPs) in 8-day-old rat forebrain synaptoneurosomes. In fact, A23187, a Ca2+ ionophore...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1991.tb06344.x
更新日期:1991-11-01 00:00:00
abstract::Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1-2 in every 1000 term infants and the devastating consequences range from cerebral palsy, epilepsy and neurological deficit to death. Cellular damage post insult occurs after a delay and is mediated by a secondary neural energy failure. AMP-activated protein ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13034
更新日期:2015-04-01 00:00:00
abstract::Nicotinic cholinergic receptor binding sites labeled by [3H]acetylcholine were measured in the cerebral cortices, thalami, striata, and hypothalami of rats lesioned by intraventricular injection of either 6-hydroxydopamine or 5, 7-dihydroxytryptamine. In addition, [3H]acetylcholine binding sites were measured in the c...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb02818.x
更新日期:1984-05-01 00:00:00
abstract::Ca2+ uptake into the endoplasmic reticulum (ER) is mediated by Ca2+ ATPase isoforms, which are all selectively inhibited by nanomolar concentrations of thapsigargin. Using ATP/Mg2+-dependent 45Ca2+ transport in rat brain microsomes, tissue sections, and permeabilized cells, as well as Ca2+ imaging in living cells we d...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01962.x
更新日期:2003-10-01 00:00:00
abstract::The characteristics of the serotonin (5-HT) output in the dorsal and median raphe nuclei of the rat were studies using in vivo microdialysis. The basal output of 5-HT increased after KCl was added to the perfusion fluid. In contrast, neither the omission of calcium ions nor the addition of 0.5 microM tetrodotoxin affe...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1993.tb13390.x
更新日期:1993-05-01 00:00:00
abstract::The lipid composition of the brain, including myelin, was studied in detail in two cases with a variant form of metachromatic leukodystrophy (multiple sulphatase deficiency type). In the white matter, the sulphatide concentration was 3-4 times higher than the normal level in both cases. There was a significant accumul...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1976.tb00310.x
更新日期:1976-11-01 00:00:00
abstract::The beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease. Despite the magnitude of reports describing a neurotoxic role of extracellular Abeta, the role for intracellular Abeta (iAbeta) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04704.x
更新日期:2007-10-01 00:00:00
abstract::A rapid and simple chromatographic procedure using HPLC with electrochemical detection is described for simultaneous determination of the substrates from precursor amino acids to metabolites related to synthesis and metabolism of three monoamine neurotransmitters--norepinephrine (NE), dopamine (DA), and 5-hydroxytrypt...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1988.tb02935.x
更新日期:1988-02-01 00:00:00
abstract::As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, the reservoirs of blood continue to inflict injury to neurovascular structures and blunt the brain repair processes. Microglia/macrophages (MMΦ) r...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12974
更新日期:2015-04-01 00:00:00
abstract::Aging was associated with an increase in the density of specific binding sites for [3H]imipramine in postmortem specimens of human hypothalamus, frontal cortex, and parietal cortex. In general, [3H]imipramine binding was not affected by factors considered difficult to control in postmortem studies, i.e., time from dea...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1985.tb07203.x
更新日期:1985-11-01 00:00:00
abstract::At the premyelinating stage, the Schwann cells of peripheral nerves are able to recognize the axon, to arrange themselves along it in a nonoverlapping manner, and finally to establish a one-to-one cell-axon relationship. The mechanism that regulates these processes is not known in detail. We found the existence of a s...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.68051853.x
更新日期:1997-05-01 00:00:00
abstract::Previous studies demonstrated that 9 kb of the rat tyrosine hydroxylase (TH) 5' flanking sequence directed appropriate spatiotemporal expression of a lacZ reporter gene to catecholaminergic cells in the CNS of transgenic mice. In the present study, specificity of transgene expression was further extended to demonstrat...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1996.67010011.x
更新日期:1996-07-01 00:00:00
abstract::Brain trauma was induced in mice using a closed head injury (CHI) model. At 1, 6 or 24 h after trauma, brains were dissected into the cortex, striatum and hippocampus. Changes in levels of processed X-box protein 1 (xbp1), glucose-regulated protein 78 (grp78), growth arrest and DNA damage-inducible gene 153 (gadd153) ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.02218.x
更新日期:2004-02-01 00:00:00
abstract::Interleukin-1β (IL-1β) is released from activated microglia and involved in the neurodegeneration of acute and chronic brain disorders, such as stroke and Alzheimer's disease, in which extracellular acidification has been shown to occur. Here, we examined the extracellular acidic pH regulation of IL-1β production, esp...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12661
更新日期:2014-05-01 00:00:00
abstract::Chronic exposure to manganese (Mn) can cause manganism, a neurodegenerative disorder similar to Parkinson's disease. The toxicity of Mn includes impairment of astrocytic glutamate transporters. 17beta-Estradiol (E2) has been shown to be neuroprotective in various neurodegenerative diseases including Parkinson's diseas...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2009.06105.x
更新日期:2009-07-01 00:00:00
abstract::'Metabolism' refers to the vast collection of chemical processes that occur within a living organism. Within this broad designation, one can identify metabolism events that relate specifically to energy homeostasis, whether they occur at the subcellular, cellular, organ, or whole organism level. This review operationa...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1111/jnc.13509
更新日期:2016-10-01 00:00:00
abstract::The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2008.05265.x
更新日期:2008-06-01 00:00:00
abstract::The 5-hydroxytryptamine (serotonin, 5-HT) type 3 (5-HT3) receptor belongs to the superfamily of Cys-loop ligand-gated ion channels, and can be either homopentameric (5-HT3A) or heteropentameric (5-HT3AB) receptor. Several modulators are known, which either inhibit or potentiate this channel, but few have any appreciab...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12146
更新日期:2013-04-01 00:00:00
abstract::We show that the expression of the gene encoding glial fibrillary acidic protein (GFAP) gene is affected by at least three cis-acting elements. A positive regulatory element that is located between nucleotides -1,631 and -1,479 can confer cell type-specific expression on a heterologous gene. A second regulatory elemen...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1991.tb03799.x
更新日期:1991-08-01 00:00:00
abstract::In human fetal spinal cord (HFSC), six additional microtubule-associated protein-2 (MAP-2) transcripts are generated by alternative splicing of two recently described exons, exon 8 and exon 13. The following three translated proteins are detected by western blot analysis: MAP-2b expressing exon 8 (MAP-2b + 8; MAP-2a),...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.68010383.x
更新日期:1997-01-01 00:00:00
abstract::The overflows of 3,4-dihydroxyphenylalanine, dopamine, noradrenaline, and 3,4-dihydroxyphenylglycol in canine portal vein superfused in vitro were studied before, during, and after depolarization of sympathetic nerve endings. The four compounds were separated from superfusate and from tissue on Sep-Pak C-18 cartridges...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb08338.x
更新日期:1992-09-01 00:00:00
abstract::We applied our in vivo fatty acid method to examine concentrations, incorporation, and turnover rates of docosahexaenoic acid (22:6 n-3) in brains of rats subject to a dietary deficiency of alpha-linolenic acid (18:3 n-3) for three generations. Adult deficient and adequate rats of the F3 generation were infused intrav...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2000.0752392.x
更新日期:2000-12-01 00:00:00
abstract::The unique modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is tightly associated with nervous system development and plasticity. The prevailing view that this large carbohydrate polymer acts as an anti-adhesive factor seems straightforward at first sight. However, during almost 25...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1111/j.1471-4159.2007.04716.x
更新日期:2007-11-01 00:00:00
abstract::Microvessels were isolated from canine cerebral cortex, and the composition of the endothelial cell membrane was investigated. Endothelial cell membranes were separated from the surrounding basement membrane, solubilized, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis in 12% gels. Staining ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1983.tb00831.x
更新日期:1983-11-01 00:00:00