Kumar Shalini, Mattan Natalia S, de Vellis Jean
Department of Neurobiology, Mental Retardation Research Center, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095-7332, USA.
Ment Retard Dev Disabil Res Rev. 2006;12(2):157-65. doi: 10.1002/mrdd.20108.
Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as the loss of myelin, results in axonal dysfunction and hence a disruption of information processing between brain regions. The major feature of leukodystrophies is the lack of proper myelin formation during early development or the onset of myelin loss late in life. These early childhood WM diseases are described as hypomyelination or dysmyelination arising from a primary block in normal myelin synthesis because of a genetic mutation expressed in oligodendrocytes, or failure in myelination secondary to neuronal or astroglial dysfunctions (van der Knaap 2001 Dev. Med. Child Neurol. 43:705-712). Here, we describe the pathophysiological parameters of Canavan disease (CD), caused by genetic mutations of the aspartoacylase (ASPA) gene, a metabolic enzyme restricted in the central nervous system (CNS) to oligodendrocytes. CD presents pathophysiological dysfunctions similar to diseases caused by myelin gene mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk viable) mutant mice. These single gene mutations have pleiotropic effects, whereby the alteration of one myelin gene expression disrupts functional expression of other oligodendrocyte genes with an outcome of hypomyelination/dysmyelination. Among all of the known leukodystrophies, CD is the first disorder, which was approved and tested for the adeno-associated virus vector (AAV)-ASPA gene therapy (Leone et al. 2000 Ann. Neurol. 48:27-38; Janson et al. 2001 Trends Neurosci. 24:706-712) without much success following the first two attempts. ASPA gene delivery attempts in animal models have shown a lowering of N-acetyl L-aspartate and a change in motor functions, while sponginess of the WM, a characteristic of CD remained unchanged (Matalon et al. 2003 Mol. Ther. 7 (5, Part 1):580-587; McPhee et al. 2005 Brain Res. Mol. Brain Res. 135:112-121) even with better viral serotype and delivery of the gene during early phase of development (Klugmann et al. 2005 Mol. Ther. 11:745-753). While different approaches are being sought for the success of gene therapy, there are pivotal developmental questions to address regarding the specific regions of the CNS and cell lineages that become the target for the onset and progression of CD symptoms from early to late stages of development.
白质（WM）中少突胶质细胞与神经元之间相互作用的破坏，如髓磷脂的丧失，会导致轴突功能障碍，进而破坏脑区之间的信息处理。脑白质营养不良的主要特征是在早期发育过程中缺乏正常的髓磷脂形成，或在生命后期开始出现髓磷脂丧失。这些儿童早期的WM疾病被描述为由于少突胶质细胞中表达的基因突变导致正常髓磷脂合成的原发性阻滞而引起的髓鞘形成不足或髓鞘形成异常，或者是继发于神经元或星形胶质细胞功能障碍的髓鞘形成失败（van der Knaap，2001年，《发育医学与儿童神经病学》43:705 - 712）。在这里，我们描述了由天冬氨酸酰基转移酶（ASPA）基因突变引起的Canavan病（CD）的病理生理参数，ASPA是一种在中枢神经系统（CNS）中仅限于少突胶质细胞的代谢酶。CD呈现出与髓磷脂基因突变引起的疾病类似的病理生理功能障碍，如佩利措伊斯 - 梅茨巴赫病（PMD），以及几种动物模型，如髓鞘缺陷大鼠（md）、jimpy（jp）、颤抖（sh）和震颤（qk viable）突变小鼠。这些单基因突变具有多效性，即一个髓磷脂基因表达的改变会破坏其他少突胶质细胞基因的功能表达，导致髓鞘形成不足/异常。在所有已知的脑白质营养不良中，CD是第一种接受腺相关病毒载体（AAV） - ASPA基因治疗并进行测试的疾病（Leone等人，2000年，《神经病学纪要》48:27 - 38；Janson等人，2001年，《神经科学趋势》24:706 - 712），但在前两次尝试后没有取得太大成功。在动物模型中进行的ASPA基因递送尝试显示N - 乙酰 - L - 天冬氨酸水平降低和运动功能改变，而WM的海绵样变性，即CD的一个特征，即使使用更好的病毒血清型并在发育早期进行基因递送，仍然没有改变（Matalon等人，2003年，《分子治疗》7（5，第1部分）:580 - 587；McPhee等人，2005年，《脑研究·分子脑研究》135:112 - 121）（Klugmann等人，2005年，《分子治疗》11:745 - 753）。虽然正在寻求不同的方法来实现基因治疗的成功，但关于CNS的特定区域和细胞谱系，仍有一些关键的发育问题需要解决，这些区域和细胞谱系在CD症状从发育早期到晚期的发生和进展过程中成为靶点。
