A new study helps to explain why people who carry mutations in a gene known as Nurr1 develop a rare, inherited form of Parkinson's disease, the most prevalent movement disorder in people over the age of 65. Protein Protects Neurons In Brain From Damage Due To Inflammation
A research team from the University of California, San Diego School of Medicine and the Salk Institute for Biological Studies in La Jolla has identified a protein in the brain of mice that protects neurons from excessive inflammation, which can lead to neurodegenerative disorders such as Parkinson's disease.
Their study, which identifies the protective function of a protein called Nurr1 and defines the pathway by which it works, will be published in the April 3 edition of the journal Cell.
Nurr1 is a transcription factor that has been known for some time to play an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are associated with familial Parkinson's disease, and the loss of dopaminergic neurons – which are the main source of dopamine in the central nervous system – is associated with the disease. Dopamine helps control multiple brain functions such as movement, attention, pleasure, emotion and motivation. The new findings have uncovered a second and previously unexpected role of the Nurr1 protein in two other cell types in the brain – microglia and astrocytes. The brain's microglia are macrophage-like cells that are active components of the immune defense in the central nervous system, while astrocytes are large star-shaped cells that normally play important support functions in the brain.
Working in mice, researchers in the Laboratory of Genetics headed by Fred H. Gage, PhD, professor at the Salk Institute, reduced the expression of Nurr1 in the brain to see how it affected the inflammatory stimulus when the brain was infused with either bacterial lipolysaccharide (LPS) – a potent activator of microglia – or with a mutant form of alpha synuclein that is associated with an early form of familial Parkinson's disease. They found that, in the absence of Nurr1, inflammation was increased in the region where dopaminergic neurons are found, resulting in a toxic effect on those neurons.
"LPS won't normally kill neurons, but the neurons died when Nurr1 was removed, so we realized that another cell type in the brain must be responding to LPS to cause this toxic effect," Gage said.
Working with isolated cells, researchers in the laboratory of Christopher Glass, MD, PhD, professor of Cellular and Molecular Medicine at UC San Diego School of Medicine and principal investigator of the study, found that microglia were the initial sensors of inflammation. "We found that if we get rid of Nurr1 in microglia, they become very sensitive to inflammatory stimulation and they over-respond, leading to the production of toxic factors." The researchers then found that factors produced by activated microglia are sensed by astrocytes. This cross-talk between the microglia and astrocytes created further inflammatory mediators that were toxic to neurons.
The second part of the study explains the molecular mechanisms that enable Nurr1 to protect the neurons by shutting off inflammatory responses in microglia and astrocytes. The researchers describe a very complex pathway made up of more than a dozen key proteins. Ultimately, the function of this pathway is to shut off expression of genes that produce inflammatory and neurotoxic mediators.
These findings are consistent with a growing appreciation of the potential roles of inflammatory responses in the central nervous system as inducers or amplifiers of a spectrum of neurodegenerative diseases that include Parkinson's disease.
"Although no prospective clinical trials have yet been performed in humans that show a benefit of inhibiting inflammation in any neurodegenerative disease, the presence of signs of inflammation in Parkinson's disease patients suggest that this could be a valuable strategy", said Glass. "The value of the present studies is that they bring to light a cell communication pathway that serves to protect the cells that make dopamine from exaggerated inflammatory responses."
Glass added that defects in any one of the proteins involved could thus increase susceptibility to neurodegenerative disease, and that understanding this communication pathway in the brain could provide potential new therapeutic targets to inhibit the production of factors that promote neuronal death.
Additional contributors to the paper include Kaoru Saijo and Jana G. Collier, UCSD Department of Cellular and Molecular Medicine; Beate Winner and Christian T. Carson, Laboratory of Genetics, Salk Institute; Leah Boyer, UCSD Biomedical Science Graduate Program and the Salk Institute; Michael G. Rosenfeld UCSD Department of Medicine and the Howard Hughes Medical Institute.
The research was supported by grants from the National Institutes of Health, the California Institute for Regenerative Medicine and the Picower Foundation. Winner is a Feodor-Lynen fellow of the Alexander von Humboldt Foundation.
“You wait till Larry comes and I tell him my theory!” The bids, duly sealed, were given into the keeping of the commissary officer to be put in his safe, and kept until the day of judgment, when all being opened in public and in the presence of the aspirants, the lowest would[Pg 188] get the contract. It was a simple plan, and gave no more opportunity for underhand work than could be avoided. But there were opportunities for all that. It was barely possible—the thing had been done—for a commissary clerk or sergeant, desirous of adding to his pittance of pay, or of favoring a friend among the bidders, to tamper with the bids. By the same token there was no real reason why the commissary officer could not do it himself. Landor had never heard, or known, of such a case, but undoubtedly the way was there. It was a question of having the will and the possession of the safe keys. "Well, I believe our boys 's all right. They're green, and they're friskier than colts in a clover field, but they're all good stuff, and I believe we kin stand off any ordinary gang o' guerrillas. I'll chance it, anyhow. This's a mighty valuable train to risk, but it ought to go through, for we don't know how badly they may need it. You tell your engineer to go ahead carefully and give two long whistles if he sees anything dangerous." "Fine-looking lot of youngsters," he remarked. "They'll make good soldiers." "That's just what he was, the little runt, and we had the devil's own time finding him. What in Sam Hill did the Captain take him for, I'd like to know? Co. Q aint no nursery. Well, the bugler up at Brigade Headquarters blowed some sort of a call, and Skidmore wanted to know what it meant. They told him that it was an order for the youngest man in each company to come up there and get some milk for his coffee tomorrow morning, and butter for his bread. There was only enough issued for the youngest boys, and if he wanted his share he'd have to get a big hustle on him, for the feller whose nose he'd put out o' joint 'd try hard to get there ahead o' him, and get his share. So Skidmore went off at a dead run toward the sound of the bugle, with the boys looking after him and snickering. But he didn't come back at roll-call, nor at tattoo, and the smart Alecks begun to get scared, and abuse each other for setting up a job on a poor, innocent little boy. Osc Brewster and Ol Perry, who had been foremost in the trick had a fight as to which had been to blame. Taps come, and he didn't get back, and then we all became scared. I'd sent Jim Hunter over to Brigade Headquarters to look for him, but he came back, and said they hadn't seen anything of him there. Then I turned out the whole company to look for him. Of course, them too-awfully smart galoots of Co. A had to get very funny over our trouble. They asked why we didn't get the right kind of nurses for our company, that wouldn't let the members stray out of their sight? Why we didn't call the children in when the chickens went to roost, undress 'em, and tuck 'em in their little beds, and sing to 'em after they'd said 'Now I lay me down to sleep?' I stood it all until that big, hulking Pete Nasmith came down with a camp-kettle, which he was making ring like a bell, as he yelled out, 'Child lost! Child lost!' Behind him was Tub Rawlings singing, 'Empty's the cradle, baby's gone.' Then I pulled off my blouse and slung it into my tent, and told 'em there went my chevrons, and I was simply Scott Ralston, and able to lick any man in Co. A. One o' their Lieutenants came out and ordered them back to their quarters, and I deployed the company in a skirmish-line, and started 'em through the brush toward Brigade Headquarters. About three-quarters o' the way Osc Brewster and Ol Perry, when going through a thicket, heard a boy boo-hooing. They made their way to him, and there was little Skidmore sitting on a stump, completely confused and fagged out. He'd lost his way, and the more he tried to find it the worse he got turned around. They called out to him, and he blubbered out: 'Yes, it's me; little Pete Skidmore. Them doddurned fools in my company 've lost me, just as I've bin tellin' 'em right along they would, durn 'em.' Osc and Ol were so tickled at finding him that they gathered him up, and come whooping back to camp, carrying him every step of the way." And the rush stopped. Cadnan waited for a second, but there was no more. "Dara is not to die," he said. Then he saw Orion hanging over him, very low in the windy sky, shaking with frost. His eyes fixed themselves on the constellation, then gradually he became aware of the sides of a cart, of the smell of straw, of the movement of other bodies that sighed and stirred beside him. The physical experience was now complete, and soon the emotional had shaped itself. Memory came, rather sick. He remembered the fight, his terror, the flaming straw, the crowd that constricted and crushed him like a snake. His rage and hate rekindled, but this time without focus—he hated just everyone and everything. He hated the wheels which jolted him, his body because it was bruised, the other bodies round him, the stars that danced above him, those unknown footsteps that tramped beside him on the road. Farewell to Jane and Caroline!" HoME大香蕉色人阁 ENTER NUMBET 0017
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The End of Suffering
Wirehead Hedonism
The Good Drug Guide
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MDMA: Utopian Pharmacology
Transhumanism: Brave New World?
Critique of Aldous Huxley's Brave New World
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