An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease
An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease
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DOI：
10.1093/hmg/11.12.1421
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发表时间：
2002-06-01
影响因子：
3.5
通讯作者：
Pearce, DA
中科院分区：
文献类型：
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作者：
Chattopadhyay, S;Ito, M;Pearce, DA
CLN3基因突变是导致神经退行性疾病巴顿病的原因；然而，这种疾病的分子基础仍不清楚。在研究Batten病的小鼠模型中，我们报告了在cln3基因敲除的小鼠血清中存在一种针对谷氨酸脱羧酶(GAD65)的自身抗体，该抗体与脑组织相关，但在正常小鼠的血清或脑中不存在。GAD65自身抗体具有抑制谷氨酸脱羧酶活性的作用。此外，由于自身抗体抑制谷氨酸脱羧酶的活性，来自cln3基因敲除小鼠的大脑降低了该酶的活性，导致来自cln3基因敲除小鼠的大脑样本的谷氨酸水平高于正常。这种升高的谷氨酸在cln3基因敲除小鼠的大脑中与突触前标志物共定位。GAD65活性降低和谷氨酸水平升高可能是cln3基因敲除小鼠星形胶质细胞明显肥大的原因，也可能是参与谷氨酸合成和利用的基因表达改变的原因之一，这些基因是谷氨酸从合成转移到利用的基础。在20名接受测试的巴顿病患者中，有20人的血清中也存在GAD65的自身抗体。身体组织对抗GAD65抗体的反应性降低，这可能是由于GAD65阳性神经元的丢失或由于自身抗体的存在而阻断了反应性表位。我们认为，对GAD65的自身免疫反应可能有助于与Batten病相关的GABA能神经元的优先损失。
Mutations in the CLN3 gene are responsible for the neurodegenerative disorder Batten disease; however, the molecular basis of this disease remains unknown. In studying a mouse model for Batten disease, we report the presence of an autoantibody to glutamic acid decarboxylase (GAD65) in cln3-knockout mice serum that associates with brain tissue but is not present in sera or brain of normal mice. The autoantibody to GAD65 has the ability to inhibit the activity of glutamic acid decarboxylase. Furthermore, brains from cln3-knockout mice have decreased activity of glutamic acid decarboxylase as a result of the inhibition of this enzyme by the autoantibody, resulting in brain samples from cln3-knockout mice having elevated levels of glutamate as compared with normal. This elevated glutamate in the brain of cln3-knockout mice co-localizes with presynaptic markers. The decreased activity of GAD65 and increased levels of glutamate may have a causative role in astrocytic hypertrophy evident in cln3-knockout mice, and in altered expression of genes involved in the synthesis and utilization of glutamate that underlie a shift from synthesis to utilization of glutamate. An autoantibody to GAD65 is also present in sera of 20 out of 20 individuals tested who have Batten disease. Postmortem tissue shows decreased reactivity to an anti-GAD65 antibody that may be due to loss of GAD65-positive neurons or due to the reactive epitope being blocked by the presence of the autoantibody. We propose that an autoimmune response to GAD65 may contribute to a preferential loss of GABAergic neurons associated with Batten disease.