C. elegans MANF Homolog Is Necessary for the Protection of Dopaminergic Neurons and ER Unfolded Protein Response.
C. elegans MANF Homolog Is Necessary for the Protection of Dopaminergic Neurons and ER Unfolded Protein Response.
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DOI：
10.3389/fnins.2018.00544
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发表时间：
2018
影响因子：
4.3
通讯作者：
Gupta BP
中科院分区：
文献类型：
--
作者：
Richman C;Rashid S;Prashar S;Mishra R;Selvaganapathy PR;Gupta BP
神经营养因子（NTFs）对哺乳动物系统中神经元的发育、功能和存活非常重要。中脑星形胶质细胞源性神经营养因子（MANF）和脑多巴胺神经营养因子（CDNF）是最近在脊椎动物中发现的两个新的NTFs家族成员，其功能是保护多巴胺能神经元。虽然这些基因在真核生物中是保守的，但它们的神经保护机制尚未完全了解。无脊椎动物中MANF/CDNF同源物的序列搜索已经确定了与MANF最相关的单一直系同源物。在这里，我们报告的MANF基因，manf-1，在线虫秀丽隐杆线虫的体内特性。我们发现manf-1突变体在多巴胺能神经元的存活率方面具有加速的、年龄依赖性的下降。这些动物还表现出增加的内质网（ER）应激，如hsp-4（ER伴侣BiP/GRP 78同源物）的报告基因表达分析所揭示的，这表明未能调节ER未折叠蛋白反应（ER-UPR）可能是多巴胺能神经变性的一个促成因素。对manf-1的表达研究表明，该基因广泛表达，其模式与hsp-4紧密匹配。与ER-UPR中manf-1的要求一致，我们发现α-突触核蛋白（Lewy小体的主要成分）的聚集体在manf-1突变动物的体壁肌肉中显著增加。总之，我们的工作证明了manf-1在C.优雅
Neurotrophic factors (NTFs) are important for the development, function, and survival of neurons in the mammalian system. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are two recently identified members of a novel family of NTFs in vertebrates that function to protect dopaminergic neurons. Although these genes are conserved across eukaryotes, their mechanism of neuroprotection is not fully understood. Sequence searches for MANF/CDNF homologs in invertebrates have identified a single ortholog that is most related to MANF. Here we report the in vivo characterization of the MANF gene, manf-1, in the nematode Caenorhabditis elegans. We found that manf-1 mutants have an accelerated, age-dependent decline in the survival of dopaminergic neurons. The animals also show increased endoplasmic reticulum (ER) stress, as revealed by reporter gene expression analysis of hsp-4, an ER chaperone BiP/GRP78 homolog, suggesting that a failure to regulate the ER unfolded protein response (ER-UPR) may be a contributing factor to dopaminergic neurodegeneration. Expression studies of manf-1 revealed that the gene is broadly expressed in a pattern that matches closely with hsp-4. Consistent with the requirements of manf-1 in the ER-UPR, we found that aggregates of α-Synuclein, a major constituent of Lewy bodies, were significantly increased in body wall muscles of manf-1 mutant animals. Overall, our work demonstrates the important role of manf-1 in dopaminergic neuronal survival and the maintenance of ER homeostasis in C. elegans.
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