Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease)
Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease)
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DOI：
10.1016/j.mcn.2019.103451
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Bradbury, Allison M.
中科院分区：
文献类型：
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作者：
Corado, Carley R.;Pinkstaff, Jason;Bradbury, Allison M.
球状细胞脑白质营养不良（GLD、克拉贝病、克拉贝病）是由编码半乳糖神经酰胺酶（GALC）的基因突变引起的。这种酶的缺乏导致中枢和外周神经系统病理学，其特征在于髓磷脂的损失和球状细胞的浸润。GLD的犬模型提供了一个翻译模型，忠实地概括了许多人类疾病的病理学。在GLD受累犬和正常犬的一生中，在血清和脑脊液（CSF）中进行靶向脂质组学分析，并在人道终点时在脑组织中进行靶向脂质组学分析，以更好地了解疾病进展并鉴定疾病的潜在生物标志物。在2周龄或4周龄时，观察到血清和CSF中的Psychosine（GALC的底物和GLD病理学的主要贡献者）分别显著升高，并在受影响动物的一生中稳定增加。重要的是，精神分裂素浓度与疾病严重程度密切相关。还发现受累动物CSF中的半乳糖神经酰胺、葡萄糖神经酰胺和乳糖神经酰胺升高，并随年龄增加。在人道终点时，发现脑组织中的Psychosine和半乳糖神经酰胺显著增加。这项研究确定了几个生物标志物，这可能是有用的治疗GLD的发展。
Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe's disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD.