生物谷報(bào)道：研究人員找到了一個(gè)新的microRNA, miR-133b,并發(fā)現(xiàn)它在中腦多巴胺能神經(jīng)元的成熟、功能,、和存活上起作用,。帕金森癥患者的中腦中，這些miR-133b細(xì)胞缺乏,。研究結(jié)果發(fā)表在最新一期的《科學(xué)》雜志上,。

帕金森癥是一種由大腦的多巴胺能神經(jīng)元產(chǎn)生的多巴胺形狀和行為有問題引起的運(yùn)動(dòng)紊亂。Jongpil Kim和同事還發(fā)現(xiàn),，miR-133b與Pitx3形成一個(gè)反饋圈,，Pitx3是中腦多巴胺能神經(jīng)元的一個(gè)關(guān)鍵的轉(zhuǎn)錄調(diào)節(jié)因子。在一片相關(guān)的研究評述中,， Sébastien S. Hébert和Bart de Strooper 寫道,，microRNA網(wǎng)絡(luò)與人類的疾病有關(guān)，包括心臟病,、癌癥,、阿爾茨海默氏病、Tourette綜合征,，現(xiàn)在被發(fā)現(xiàn)也與帕金森癥有關(guān),。他們提議，這個(gè)發(fā)現(xiàn)以及在神經(jīng)退化疾病領(lǐng)域的其他發(fā)現(xiàn)也許能幫助闡明microRNA 涉及這類疾病的程度,，他們指出,，“microRNA做為治療疾病的靶標(biāo)仍是一個(gè)極具挑戰(zhàn)的課題”,。

Fig. 1. Dicer is essential for the midbrain DN phenotype. (A) Floxed Dicer conditional knockout ES cultures (flx/flx) were differentiated by the EB method, transduced with Cre or control green fluorescent protein (GFP) lentivirus, and analyzed by immunostaining with antibodies specific for TH (red), TujI (green), and GABA (blue). Cultures transduced with a lentiviral Cre vector (vCre) but not control GFP lentivirus (vGFP) were essentially devoid of TH+ neurons, whereas TujI+ and GABA+ cells were reduced by approximately 40 to 60%. (n = 3 independent samples per group). Scale bar, 100 µm. Data represent mean ± SEM; analysis of variance (ANOVA) test, *P < 0.05. (B) The Dicer deletion phenotype, as in (A), can be "rescued" by transfection of midbrain-derived small RNAs (<200 base pairs) but not large RNAs (>200 base pairs). Two independent experiments of three sets each were performed, with 10 visual fields per set; data represent mean ± SEM; ANOVA test, **P < 0.01. (C) Immunostaining of brain sections from 8-week-old DATCRE/+:Dicer flox/flox mice for TH demonstrates loss of 90% of midbrain DNs in the substantia nigra (SN) and ventral tegmental area (VTA) and their axonal projections to the striatum relative to control littermates (DATCRE/+:Dicer flox/+)(n = 3 for each genotype). Scale bars, 200 µm. (D) Locomotor activity of DATCRE/+:Dicerflox/flox mice in the open field. The total distance traveled was significantly decreased in DATCRE/+:Dicerflox/flox mice (n = 4 for each genotype). Data represent mean ± SEM; Student's t test, *P < 0.05,**P < 0.01. [View Larger Version of this Image (197K JPEG file)]

原文出處：

Science    31 August 2007         Vol 317, Issue 5842

A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons

Jongpil Kim, Keiichi Inoue, Jennifer Ishii, William B. Vanti, Sergey V. Voronov, Elizabeth Murchison, Gregory Hannon, and Asa Abeliovich
Science 31 August 2007: 1220-1224.
MicroRNAs are required for the maturation and function of midbrain dopamine neurons, and loss of a particular miRNA may underlie Parkinson抯 disease.
Abstract »|   Full Text »|   PDF »|   Supporting Online Material »|  

作者簡介：

Asa Abeliovich, M.D., Ph.D.
Assistant Professor of Pathology and Neurology

Research Summary
Molecular mechanisms of neurodegeneration and the life cycle of dopamine neurons.

We are studying the molecular bases of midbrain dopamine neuron development, function and survival. Midbrain dopamine neurons are thought to play key roles in learned and addictive behaviors, and degeneration of these neurons underlies Parkinson's disease.

A focus of the lab is to understand the mechanisms by which mutations in Parkinson’s disease-related genes, such as a-synuclein and parkin, lead to midbrain dopamine neuron dysfunction and eventual demise. We are also particularly interested in the normal cellular roles of these genes. We use a combination of molecular biological, cellular, and mouse genetic approaches to this end.

In a second project, we are characterizing molecules that play a important roles in the specification and late development of dopamine neurons using an in vitro culture system. Embryonic stem cells have been shown to give rise to dopamine neurons in response to a set of extrinsic cues such as sonic hedgehog and FGF8. Furthermore, a few intrinsic cellular factors, such as nurr1, have been implicated in the generation of dopamine neurons. We are using molecular biological tools to investigate the mechanism by which such intrinsic signals determine midbrain dopamine neuron fate.

Selected Publications

1. Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W.-H., Verdugo, J. M. G., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A. (1999). Mice lacking a-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252.

2. Staropoli, J. F., McDermott, C., Martinat, C., Schulman, B., Demireva, E, and Abeliovich, A. (2003). Parkin is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity. Neuron 37: 735-749.

窗體頂端

窗體底端

Honors and Awards
1988 Medical Scientist Training Program Predoctoral Fellowship, Harvard Medical School
2001 Culpeper Scholar, Rockefeller Brothers Foundation
2001 Beeson Scholar, American Federation for Aging Research
2001 Mathissen Foundation Award, Columbia University

Keywords

Parkinson's disease, gene expression, gene mutation, genetic disorder, neurogenetics, neuropathology, dopamine, neural degeneration, neuron, protein structure function, ubiquitin, gene targeting, immunocytochemistry, laboratory mouse.

相關(guān)基因：

MIRN133B

Official Symbol MIRN133B and Name: microRNA 133b [Homo sapiens]
Other Aliases: MIR133B, mir-133b
Chromosome: 6
MIM: 610946
GeneID: 442890