Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · May 2009
Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility.
Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. ⋯ Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.
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Proc. Natl. Acad. Sci. U.S.A. · May 2009
Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.
New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. ⋯ We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.
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Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. ⋯ Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2009
Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock.
When food availability is restricted to a particular time each day, mammals exhibit food-anticipatory activity (FAA), a daily increase in locomotor activity preceding the presentation of food. Considerable historical evidence suggests that FAA is driven by a food-entrainable circadian clock distinct from the master clock of the suprachiasmatic nucleus. ⋯ FAA is thus independent of the known circadian clock. Our results indicate either that FAA is not the output of an oscillator or that it is the output of a circadian oscillator different from known circadian clocks.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2009
A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice.
The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. ⋯ TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.