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首页> 外文期刊>Neurobiology of disease >Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation
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Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation

机译：过氧化物酶体多功能蛋白2缺乏症引起浦肯野细胞的神经炎症和变性，而与非常长链脂肪酸的积累无关

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摘要

Although peroxisome biogenesis and β-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal β-oxidation, in all neural cells (Nestin-Mfp2-/-) or in oligodendrocytes (Cnp-Mfp2-/-) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome β-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal β-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation.
机译：尽管过氧化物酶体的生物发生和β-氧化紊乱因其神经发育缺陷而众所周知，但越来越多的人将这些疾病的患者诊断为神经退行性病变。为了研究这些患者神经退行性病变的细胞机制，我们开发了一种小鼠模型，其在所有神经细胞中均缺乏过氧化物酶体β-氧化的中心酶多功能蛋白2（MFP2，也称为D双功能蛋白）。 -/-）或少突胶质细胞（Cnp-Mfp2-/-）中，并将这些模型与已经建立的一般Mfp2基因敲除进行比较。 Nestin-Mfp2敲除小鼠但不是Cnp-Mfp2敲除小鼠会产生运动障碍和共济失调，类似于一般突变体。运动能力的下降与小脑浦肯野细胞轴突的死亡有关，这是在浦肯野细胞丧失和小脑萎缩之前。这紧密模拟了患有轻度过氧化物酶体β-氧化疾病的患者的脊髓小脑共济失调。但是，一般的基因敲除小鼠的寿命比Nestin-Mfp2基因敲除小鼠要短得多，这与先天免疫系统激活方面的差异平行。在一般突变体中，整个大脑会发生强烈的慢性促炎反应，而从神经细胞中清除MFP2则会导致轻微的神经炎症。炎症反应的程度和小脑变性都与超长链脂肪酸（过氧化物酶体β-氧化的底物）的水平无关。总之，MFP2在成年大脑中具有多项任务，包括维持Purkinje细胞和预防神经炎症，但这不是由其在少突胶质细胞中的活性或在长链脂肪酸降解中的作用所介导的。

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