Research for the pathophysiology of adrenoleukodystrophy and therapeutic measures

利用肾上腺脑白质营养不良(ALD)基因敲除小鼠，研究ALD的病理生理机制，探讨ALD的治疗措施。单独表达超长链酰辅酶A合成酶并不能纠正β氧化超长链脂肪酸的损伤，提示A+DP是超长链脂肪酸发挥功能所必需的。ALDP缺陷小鼠体内VLACS的含量降低，提示ALDP在VLACS的过氧化定位中起一定作用。洛伐他汀可纠正ALD患者血浆中VLCFA的积聚，但不能纠正ALDP缺陷小鼠脑和脊髓等组织中的VLCFA积聚。将小鼠神经干细胞C17-2注入新生ALDP缺陷小鼠的脑室。VLCFA在全脑的积聚没有得到纠正，可能是由于植入的细胞数量较少所致。

The pathophysiology of adrenoleukodystrophy (ALD) was investigated and the therapeutic measures for ALD was examined, using the ALD gene-knockout mice. The additional expression of very long chain acyl-CoA synthetase (VLACS) alone did not correct the impairment of β -oxidation of very long chain fatty acid (VLCFA) in ALD protein (ALDP)-deficient cells, suggesting that A+DP is required for VLCS to function. The amount of VLACS in the peroxisomal fraction was lowered in the ALDP-deficient mouse, suggesting that ALDP plays a role in the peroxisomal localization of VLACS.The function of inflammatory cells was examined in the ALDP-deficient mouse. The ALDP-deficiency did not enhance the activation of microglia and macrophage by interferon-γ and lipopolysaccharide.Lovastatin corrects the accumulation of VLCFA in the plasma of ALD patients, but did not that in the tissues including the brain and spinal cord of ALDP-deficient mice.The murine neural stem cells, C17-2, was injected into the ventricle of the newborn ALDP-deficient mice. The accumulation of VLCFA was not corrected in the whole brain probably due to the small number of the implanted cells.