Absence of miRNA-146a Differentially Alters Microglia Function and Proteome

Background: MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Methods: By sorting CNS resident cells, microglia were the main cellular source of miR-146a. Therefore, we investigated microglia function and phenotype in miR-146a knock-out (KO) mice, analyzed the proteome of KO and wild-type (WT) microglia by LC-MS/MS, and examined miR-146a expression in different brain lesions of patients with multiple sclerosis (MS). Results: When stimulated with LPS or myelin in vitro, microglia from KO mice expressed higher levels of IL-1β, TNF, IL-6, IL-10, CCL3, and CCL2 compared to WT. Stimulation increased migration and phagocytosis of WT but not KO microglia. CD11c+ microglia were induced by cuprizone (CPZ) in the WT mice but less in the KO. The proteome of ex vivo microglia was not different in miR-146a KO compared to WT mice, but CPZ treatment induced differential and reduced protein responses in the KO: GOT1, COX5b, CRYL1, and cystatin-C were specifically changed in KO microglia. We explored discriminative features of microglia proteomes: sparse Partial Least Squares-Discriminant Analysis showed the best discrimination when control and CPZ-treated conditions were compared. Cluster of ten proteins separated WT and miR-146a KO microglia after CPZ: among them were sensomes allowing to perceive the environment, Atp1a3 that belongs to the signature of CD11c+ microglia, and proteins related to inflammatory responses (S100A9, Ppm1g). Finally, we examined the expression of miR-146a and its validated target genes in different brain lesions of MS patients. MiR-146 was upregulated in all lesion types, and the highest expression was in active lesions. Nineteen of 88 validated target genes were significantly changed in active lesions, while none were changed in NAWM. Conclusion: Our data indicated that microglia is the major source of miR-146a in the CNS. The absence of miR-146a differentially affected microglia function and proteome, and miR-146a may play an important role in gene regulation of active MS lesions

Road with Wilson House? in background, Castlecrag, New South Wales, ca. 1922, [2] [picture].

Title from acquisition documentation.; Part of the collection: Eric Milton Nicholls collection.; Condition: Fair.; Also available in electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3993515; Purchased from Marie and Glynn Nicholls, 2006

Multiple sclerosis in Iceland from 1900 to 2000: A total population study.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageThe epidemiology of multiple sclerosis (MS) in Iceland in1900-2000 is presented. The incidence increased significantly from 2.58×10(5) in 1950 to 5.06×10(5) in 2000 (from 2.71 to 7.03×10(5) for women and from 2.55 to 3.10×10(5) for men) with a yearly increase by a factor of 1.0816 per year for women and 1.01207 per year for men (Poisson regression analysis). Prevalence standardized to the European standard population rose from 29.9×10(5) in 1950 to 131.7×10(5) in 2000. The standardized prevalence was constantly higher amongst women (42.8-181.6×10(5) vs. 16.7-81.5×10(5) for men) with a female to male ratio of 2.6 in 1950 and in 2000. Mean age at onset for all patients increased from 27.8 years in 1950 to 30.7 years in 2000 (from 27.0 to 30.1 years for women and from 28.6 to 32.2 years for men). Children and adolescents (<18 years) were 9.6% of all, of whom 60% were diagnosed after 1970. Mean age of onset for children and adolescents was 14.7 years (9-17 years, 95% CI 4.2 years). The rise in incidence and prevalence can have multiple explanations, including diagnosis of milder forms of MS, increased awareness of MS in the older population, better diagnostic measures and longer survival but the authors find it likely that there has been a true rise in the MS incidence

Generation of High-Yield, Functional Oligodendrocytes from a c- myc Immortalized Neural Cell Line, Endowed with Staminal Properties

Neural stem cells represent a powerful tool to study molecules involved in pathophysiology of Nervous System and to discover new drugs. Although they can be cultured and expanded in vitro as a primary culture, their use is hampered by their heterogeneity and by the cost and time needed for their preparation. Here we report that mes-c-myc A1 cells (A1), a neural cell line, is endowed with staminal properties. Undifferentiated/proliferating and differentiated/non-proliferating A1 cells are able to generate neurospheres (Ns) in which gene expression parallels the original differentiation status. In fact, Ns derived from undifferentiated A1 cells express higher levels of Nestin, Kruppel-like factor 4 (Klf4) and glial fibrillary protein (GFAP), markers of stemness, while those obtained from differentiated A1 cells show higher levels of the neuronal marker beta III tubulin. Interestingly, Ns differentiation, by Epidermal Growth Factors (EGF) and Fibroblast Growth Factor 2 (bFGF) withdrawal, generates oligodendrocytes at high-yield as shown by the expression of markers, Galactosylceramidase (Gal-C) Neuron-Glial antigen 2 (NG2), Receptor-Interacting Protein (RIP) and Myelin Basic Protein (MBP). Finally, upon co-culture, Ns-A1-derived oligodendrocytes cause a redistribution of contactin-associated protein (Caspr/paranodin) protein on neuronal cells, as primary oligodendrocytes cultures, suggesting that they are able to form compact myelin. Thus, Ns-A1-derived oligodendrocytes may represent a time-saving and low-cost tool to study the pathophysiology of oligodendrocytes and to test new drugs

A follow-up study of Nordic multiple sclerosis candidate gene regions

In this study, the results from three Nordic linkage disequilibrium screens in multiple sclerosis (MS) were investigated, in a new sample set of 314 Nordic MS trios from Denmark, Norway, Sweden and Iceland. Among 30 non-HLA and two HLA microsatellite markers individually genotyped, eight markers displayed distorted transmission with uncorrected P-value <0.05, ranked in this order: D6S2443 (6p21.32, HLA class II) (P corrected =0.01), D2S2201 (2p24), D19S552 (19q13), D3S3584 (3q21), D17S975 (17q11), DIS2627 (1p22), D6S273 (6p21.33, HLA class III) and D72S1051 (12q23). These non-HLA regions need further investigation as possible MS candidate gene regions in our population