Ataxia with loss of Purkinje cells in a mouse model for Refsum disease
Ataxia with loss of Purkinje cells in a mouse model for Refsum disease
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DOI：
10.1073/pnas.0806066105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Brites, Pedro
中科院分区：
文献类型：
--
作者：
Ferdinandusse, Sacha;Zomer, Anna W. M.;Brites, Pedro
Refsum病是由于过氧化体α-氧化系统的第一种酶--植酰辅酶A羟基酶(PHYH)缺乏，导致支链脂肪酸植酸积聚所致。主要临床症状为多发性神经病、小脑性共济失调和视网膜色素变性。为了研究Refsum病的发病机制，我们培育了一只Phyh基因敲除小鼠并对其进行了鉴定。我们研究了在Phyh(-/-)小鼠饲料中添加植酸前体植物醇后植酸蓄积的病理效应。植酸蓄积导致体重减轻、肝脏脂肪变性和精原细胞丢失的睾丸萎缩。使用SHIRPA方案的表型评估和随后使用T型台系统的自动步态分析显示，步态不稳定，前爪和后爪的爪印面积显著减少，对后爪的支撑基础也减少。中枢神经系统的组织化学分析显示星形胶质细胞和钙结合蛋白表达上调。此外，还观察到小脑中浦肯野细胞的丢失。中枢神经系统未见脱髓鞘现象。运动神经传导速度测量显示为周围神经病变。我们的结果表明，在小鼠中，高水平的植酸会导致周围神经病变和浦肯野细胞丢失的共济失调。这些发现为Refsum病的病理生理学提供了重要的见解。
Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal a-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.