生物谷報(bào)道：最近,，來(lái)自哥倫比亞大學(xué)的研究人員Asa Abeliovich和他同事發(fā)現(xiàn),，腦內(nèi)一個(gè)已知蛋白的突變是通過(guò)阻止神經(jīng)元細(xì)胞生長(zhǎng)和分支來(lái)發(fā)揮其損害作用的,該蛋白在一類(lèi)帕金森癥（PD）中起重要作用,。他們精確地了解到由突變的LRRK2基因表達(dá)的該蛋白的非正常功能，以及它是如何影響神經(jīng)元并最終導(dǎo)致細(xì)胞死亡,。多巴胺神經(jīng)元的丟失是PD病理現(xiàn)象中的主要部分,，并且多巴胺神經(jīng)元之間失去聯(lián)系是PD發(fā)展的早期特點(diǎn)。這一發(fā)現(xiàn)將被發(fā)表在2006年11月22日的神經(jīng)元雜志上,，該雜志屬于細(xì)胞出版社,。
    LRRK2已被發(fā)現(xiàn)在家族性PD中出現(xiàn)突變，它是‘亮氨酸豐富區(qū)重復(fù)激酶2’的縮寫(xiě),，這意味著LRRK2蛋白是一個(gè)激酶,，它通過(guò)添加磷酸到其它蛋白上從而激活這些蛋白的活性,。

研究人員將LRRK2突變體引入到體外培養(yǎng)的神經(jīng)元中，神經(jīng)元的生長(zhǎng)和分支都會(huì)降低,，神經(jīng)元生存率下降,。研究人員分析了突變蛋白的功能，發(fā)現(xiàn)它是該蛋白激發(fā)激酶作用的部分,，是酶缺失功能的核心環(huán)節(jié),。由突變LRRK2引發(fā)PD的病理學(xué)表現(xiàn)也包括在神經(jīng)元里形成非正常沉積物或者稱(chēng)為內(nèi)含體。與之一致的是,，Abeliovich和其同事也在體外培養(yǎng)的腦細(xì)胞中發(fā)現(xiàn)類(lèi)似的內(nèi)含體,。而且，當(dāng)研究人員把LRRK2突變體引入到成年大鼠腦中,，他們也發(fā)現(xiàn)類(lèi)似體外培養(yǎng)的情況：該突變體阻止多巴胺神經(jīng)元生長(zhǎng)及誘導(dǎo)產(chǎn)生非正常的內(nèi)含體,。最后，當(dāng)研究人員把LRRK2突變體引入到胚胎大鼠腦中,，他們發(fā)現(xiàn)在腦發(fā)育過(guò)程中在神經(jīng)細(xì)胞交流中起作用的分支的數(shù)量和長(zhǎng)度都降低,。
    研究人員指出他們的發(fā)現(xiàn)為研究早期LRRK2相關(guān)疾病提供了一個(gè)有用的動(dòng)物模型，他們引入突變體的技術(shù)可以被用來(lái)制造形成PD的哺乳動(dòng)物模型,。這些細(xì)胞和動(dòng)物模型可能會(huì)促進(jìn)發(fā)現(xiàn)治療LRRK2相關(guān)疾病的有效方法,。

原文出處：

Neuron November 22, 2006: 52 (4)

The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology
David MacLeod, Julia Dowman, Rachel Hammond, Thomas Leete, Keiichi Inoue, and Asa Abeliovich
[Summary] [Full Text] [PDF] [Supplemental Data]

http://www.neuron.org/content/article/fulltext?uid=PIIS0896627306008075

作者簡(jiǎn)介：

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

部分英文原文：
　　　　The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology

Mutations in LRRK2 underlie an autosomal-dominant, inherited form of Parkinson's disease (PD) that mimics the clinical features of the common “sporadic” form of PD. The LRRK2 protein includes putative GTPase, protein kinase, WD40 repeat, and leucine-rich repeat (LRR) domains of unknown function. Here we show that PD-associated LRRK2 mutations display disinhibited kinase activity and induce a progressive reduction in neurite length and branching both in primary neuronal cultures and in the intact rodent CNS. In contrast, LRRK2 deficiency leads to increased neurite length and branching. Neurons that express PD-associated LRRK2 mutations additionally harbor prominent phospho-tau-positive inclusions with lysosomal characteristics and ultimately undergo apoptosis.

Parkinson's disease is the second most common neurodegenerative disease, typically presenting as a progressive movement disorder with slowness, rigidity, gait difficulty, and tremor at rest. The pathological hallmarks of PD include the loss of dopamine (DA) neurons in the substantia nigra (SN) of the ventral midbrain and the presence of intracytoplasmic protein aggregates, termed Lewy bodies (LB), composed of the synaptic vesicle-associated protein α-synuclein (αSyn), ubiquitin, and other components. An early feature of PD pathology is the loss of dopaminergic axonal processes that extend from the SN to the striatum, preceding the eventual loss of DA neuron cell bodies (Abeliovich et al., 2006).

Recently, autosomal-dominant mutations in leucine-rich repeat kinase-2 (LRRK2; also PARK8, dardarin, OMIM 609007) were described in a familial Parkinsonism syndrome that mimics the clinical and pathological features of the common, sporadic form of PD (Paisan-Ruiz et al., 2004, Zimprich et al., 2004). Pathological examination of patients with LRRK2 mutations has revealed dopamine (DA) neuron degeneration in the substantia nigra (SN) of the ventral midbrain, as expected, but also surprising heterogeneity regarding other pathological features: some cases harbor αSyn-positive Lewy body (LB) intracytoplasmic aggregates typical of sporadic PD and other synucleinopathies; whereas other cases either lack LB aggregates, display widespread LB pathology in the cerebral cortex, or harbor tau-positive axonal inclusions (Wszolek et al., 2004).

LRRK2 encodes a multidomain protein that includes a Rho/Ras-like GTPase domain (termed Roc, for Ras in complex proteins), a protein kinase domain related to the mixed lineage kinase (MLK) family (Manning et al., 2002), as well as WD40-repeat and LRR domains. An additional domain C-terminal to the GTPase domain, termed COR (for carboxy-terminal of Ras), is of unknown function. PD-associated mutations in LRRK2 appear to fall throughout all of the identified structural segments. Interestingly, the G2019S and I2020T mutations are both predicted to alter a highly conserved region of the kinase domain termed the “activation loop,” based on structural homology to other protein kinases (Davies et al., 2002).

Here we show that mammalian LRRK2 regulates neurite maintenance and neuronal survival. Neurons that express disease-associated mutant forms of LRRK2 display reduced neurite process length and complexity, tau-positive inclusions with lysosomal features, and ultimately apoptotic cell death. In contrast, neurons deficient in LRRK2 harbor extended neuritic processes with increased branching.