生物谷报道：最近，来自哥伦比亚大学的研究人员Asa Abeliovich和他同事发现，脑内一个已知蛋白的突变是通过阻止神经元细胞生长和分支来发挥其损害作用的,该蛋白在一类帕金森症（PD）中起重要作用。他们精确地了解到由突变的LRRK2基因表达的该蛋白的非正常功能，以及它是如何影响神经元并最终导致细胞死亡。多巴胺神经元的丢失是PD病理现象中的主要部分，并且多巴胺神经元之间失去联系是PD发展的早期特点。这一发现将被发表在2006年11月22日的神经元杂志上，该杂志属于细胞出版社。
LRRK2已被发现在家族性PD中出现突变，它是‘亮氨酸丰富区重复激酶2’的缩写，这意味着LRRK2蛋白是一个激酶，它通过添加磷酸到其它蛋白上从而激活这些蛋白的活性。
研究人员将LRRK2突变体引入到体外培养的神经元中，神经元的生长和分支都会降低，神经元生存率下降。研究人员分析了突变蛋白的功能，发现它是该蛋白激发激酶作用的部分，是酶缺失功能的核心环节。由突变LRRK2引发PD的病理学表现也包括在神经元里形成非正常沉积物或者称为内含体。与之一致的是，Abeliovich和其同事也在体外培养的脑细胞中发现类似的内含体。而且，当研究人员把LRRK2突变体引入到成年大鼠脑中，他们也发现类似体外培养的情况：该突变体阻止多巴胺神经元生长及诱导产生非正常的内含体。最后，当研究人员把LRRK2突变体引入到胚胎大鼠脑中，他们发现在脑发育过程中在神经细胞交流中起作用的分支的数量和长度都降低。
研究人员指出他们的发现为研究早期LRRK2相关疾病提供了一个有用的动物模型，他们引入突变体的技术可以被用来制造形成PD的哺乳动物模型。这些细胞和动物模型可能会促进发现治疗LRRK2相关疾病的有效方法。
原文出处：
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
作者简介：
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.
