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71.
72.
B Dehay M Martinez-Vicente A Ramirez C Perier C Klein M Vila E Bezard 《Autophagy》2012,8(9):1389-1391
Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates and diminished lysosomal-mediated clearance of autophagosomes (AP). Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration. 相似文献
73.
de Mota N Iturrioz X Claperon C Bodineau L Fassot C Roques BP Palkovits M Llorens-Cortes C 《Journal of neurochemistry》2008,106(1):416-428
Aminopeptidase A (APA) generated brain angiotensin III, one of the main effector peptides of the brain renin angiotensin system, exerting a tonic stimulatory effect on the control of blood pressure in hypertensive rats. The distribution of APA in human brain has not been yet studied. We first biochemically characterized human brain APA (apparent molecular mass of 165 and 130 kDa) and we showed that the human enzyme exhibited similar enzymatic characteristics to recombinant mouse APA. Both enzymes had similar sensitivity to Ca(2+). Kinetic studies showed that the K(m) (190 mumol/L) of the human enzyme for the synthetic substrate-l-glutamyl-beta-naphthylamide was close from that of the mouse enzyme (256 mumol/L). Moreover, various classes of inhibitors including the specific and selective APA inhibitor, (S)-3-amino-4-mercapto-butyl sulfonic acid, had similar inhibitory potencies toward both enzymes. Using (S)-3-amino-4-mercapto-butyl sulfonic acid, we then specifically measured the activity of APA in 40 microdissected areas of the adult human brain. Significant heterogeneity was found in the activity of APA in the various analyzed regions. The highest activity was measured in the choroids plexus and the pineal gland. High activity was also detected in the dorsomedial medulla oblongata, in the septum, the prefrontal cortex, the olfactory bulb, the nucleus accumbens, and the hypothalamus, especially in the paraventricular and supraoptic nuclei. Immunostaining of human brain sections at the level of the medulla oblongata strengthened these data, showing for the first time a high density of immunoreactive neuronal cell bodies and fibers in the motor hypoglossal nucleus, the dorsal motor nucleus of the vagus, the nucleus of the solitary tract, the Roller nucleus, the ambiguus nucleus, the inferior olivary complex, and in the external cuneate nucleus. APA immunoreactivity was also visualized in vessels and capillaries in the dorsal motor nucleus of the vagus and the inferior olivary complex. The presence of APA in several human brain nuclei sensitive to angiotensins and involved in blood pressure regulation suggests that APA in humans is an integral component of the brain renin angiotensin system and strengthens the idea that APA inhibitors could be clinically tested as an additional therapy for the treatment of certain forms of hypertension. 相似文献
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75.
Valant C Gregory KJ Hall NE Scammells PJ Lew MJ Sexton PM Christopoulos A 《The Journal of biological chemistry》2008,283(43):29312-29321
Many G protein-coupled receptors (GPCRs) possess allosteric binding sites distinct from the orthosteric site utilized by their cognate ligands, but most GPCR allosteric modulators reported to date lack signaling efficacy in their own right. McN-A-343 (4-(N-(3-chlorophenyl)carbamoyloxy)-2-butynyltrimethylammonium chloride) is a functionally selective muscarinic acetylcholine receptor (mAChR) partial agonist that can also interact allosterically at the M(2) mAChR. We hypothesized that this molecule simultaneously utilizes both an allosteric and the orthosteric site on the M(2) mAChR to mediate these effects. By synthesizing progressively truncated McN-A-343 derivatives, we identified two, which minimally contain 3-chlorophenylcarbamate, as pure allosteric modulators. These compounds were positive modulators of the orthosteric antagonist N-[(3)H]methylscopolamine, but in functional assays of M(2) mAChR-mediated ERK1/2 phosphorylation and guanosine 5'-3-O-([(35)S]thio)triphosphate binding, they were negative modulators of agonist efficacy. This negative allosteric effect was diminished upon mutation of Y177A in the second extracellular (E2) loop of the M(2) mAChR that is known to reduce prototypical allosteric modulator potency. Our results are consistent with McN-A-343 being a bitopic orthosteric/allosteric ligand with the allosteric moiety engendering partial agonism and functional selectivity. This finding suggests a novel and largely unappreciated mechanism of "directed efficacy" whereby functional selectivity may be engendered in a GPCR by utilizing an allosteric ligand to direct the signaling of an orthosteric ligand encoded within the same molecule. 相似文献
76.
The Hackensack Meadowlands District is a large heavily degraded, brackish marsh system in the urbanized northeastern region
of New Jersey, USA. Six study sites were used, three of which were restored (Mill Creek, Skeetkill Creek and Vince Lombardi),
and three others were unrestored (Richard DeKorte Park, Cedar Creek and Kingsland Creek). Highly significant differences were
found with respect to snail abundance and gill parasite abundance. In the three restored sites, significantly more Littoridinops tenuipes were found, and Fundulus heteroclitus had significantly more digenean trematode metacercariae gill infections than at unrestored sites. As habitat quality improves
following restoration, the number of suitable digenean trematode parasite hosts multiplies as substrate for benthic invertebrates
(first intermediate host) increases and usage by other species, such as Fundulus spp. (second intermediate host), is encouraged, which then attracts more wading birds (definitive host). Though the restoration
process enhances trophic complexity, including primary consumers (gastropods), secondary consumers (fish) and tertiary consumers
(wading birds), and ultimately parasite diversity, restoration also helps facilitate parasite life cycles. 相似文献
77.
At proestrous, the sensitivity of gonadotrophs to gonadotrophin-releasing hormone (GnRH) increases with repeated exposure
to GnRH, a process known as self-priming. An apparently similar phenomenon can also occur in peptidergic neurons; activity-dependent
oxytocin release from dendrites can be potentiated by oxytocin itself. In the brain, such priming actions have the potential
to alter the strength of communication between neuronal populations for a very prolonged period. In the case of both oxytocin
neurons and gonadotrophs, priming appears to involve an augmentation of a readily releasable pool of vesicles.
Special issue article in honor of George Fink. 相似文献
78.
79.
Weis Judith S. Windham Lisamarie Santiago-Bass Celine Weis Peddrick 《Wetlands Ecology and Management》2002,10(1):71-84
Marsh vegetation plays an important role in trophic ecology of estuaries. Once broken down to detritus, it is an important food source for manyorganisms. In Atlantic Coast marshes, the reed Phragmites australis hasbeen invading many areas once dominated by smooth cordgrass, Spartina alterniflora. In this study we evaluated the growth of and trophictransfer of metals to estuarine invertebrates when fed diets of detritus fromthese different plant species. Decaying leaves from populations of Phragmites, natural Spartina, and restored Spartina from boththe Hackensack Meadowlands, New Jersey, and the more pristineAccabonac Harbor of East Hampton, New York, were collected from themarsh surface in the spring. Decaying leaves were pureed and fed to thefiddler crabs Uca pugnax and U. pugilator, and to the grassshrimp Palaemonetes pugio. In fiddler crabs we monitored limbregeneration, molting and weight. U. pugilator regenerated limbs andmolted equally well on all six diets. Most of the U. pugnax arrestedgrowth midway through regeneration on all 6 diets. A repeat experimentwith smaller crabs, which did complete the process, found no consistentdifferences among the six diets and control food, although control food andPhragmites detritus had higher N concentrations than the Spartinadetritus. Grass shrimp fed all six diets did not survive beyond 3 weeks. Inanother experiment using HM sediments from each vegetation type(containing detritus, meiofauna, and microflora), survival was equally highamong treatments and the shrimp fed sediments from the restored Spartina site or control food grew better than those fed sediments fromthe Phragmites or natural Spartina sites. Although metalconcentrations in detritus varied between sites and plant species, the crabsof each group did not differ in metal concentrations after the feedingexperiment. Our data do not support the general assumption that Phragmites leaf detritus is of poorer nutritional quality than Spartinaalterniflora leaf detritus to estuarine consumers. 相似文献
80.