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性别依赖性淀粉样前体样蛋白 2 在 SOD1-G37R 转基因 MND 小鼠模型中的作用。

Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND.

机构信息

Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia.

Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.

出版信息

Cell Mol Life Sci. 2021 Oct;78(19-20):6605-6630. doi: 10.1007/s00018-021-03924-5. Epub 2021 Sep 2.

DOI:10.1007/s00018-021-03924-5
PMID:34476545
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8558206/
Abstract

Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2-/- mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

摘要

运动神经元病（MND）是一种神经退行性疾病，其特征是运动神经元进行性破坏、肌肉瘫痪和死亡。淀粉样前体蛋白（APP）在中枢神经系统中高度表达，并已被证明可调节 MND 的疾病结果。APP 是基因家族的一部分，该基因家族包括淀粉样前体样蛋白 1（APLP1）和 2（APLP2）基因。在本研究中，我们通过检查人类脊髓组织并将 APLP2 敲除小鼠与超氧化物歧化酶 1（SOD1-G37R）转基因 MND 小鼠模型杂交，研究了 APLP2 在 MND 中的作用。我们发现，在 MND 人类病例的脊髓中，APLP2 的表达升高，并且人类疾病的这一特征在 SOD1-G37R 小鼠的 MND 样表型进展的终末期得到重现。SOD1-G37R 小鼠中 APLP2 的缺失显著延迟了疾病进展并增加了雌性 SOD1-G37R 小鼠的存活。分子和生化分析表明，雌性 SOD1-G37R：APLP2-/- 小鼠表现出神经肌肉接头的神经支配改善，肌肉纤维萎缩得到改善，并且腓肠肌中的 APP 蛋白表达水平增加。这些结果表明 APLP2 在突变 SOD1 介导的 MND 中具有性别依赖性作用，并进一步支持 APP 家族作为进一步研究 MND 的病因和调节的潜在靶点。

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