Richman Cory, Rashid Sabih, Prashar Shreya, Mishra Ram, Selvaganapathy P Ravi, Gupta Bhagwati P
Department of Biology, McMaster University, Hamilton, ON, Canada.
Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, Canada.
Front Neurosci. 2018 Aug 10;12:544. doi: 10.3389/fnins.2018.00544. eCollection 2018.
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 characterization of the MANF gene, , in the nematode . We found that 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 , 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 revealed that the gene is broadly expressed in a pattern that matches closely with . Consistent with the requirements of 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 mutant animals. Overall, our work demonstrates the important role of in dopaminergic neuronal survival and the maintenance of ER homeostasis in .
神经营养因子（NTFs）对哺乳动物系统中神经元的发育、功能及存活至关重要。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）是脊椎动物中神经营养因子新家族最近鉴定出的两个成员，其作用是保护多巴胺能神经元。尽管这些基因在真核生物中是保守的，但其神经保护机制尚未完全了解。在无脊椎动物中对MANF/CDNF同源物进行序列搜索，已鉴定出一个与MANF最相关的单一直系同源物。在此，我们报告线虫中MANF基因的特征。我们发现MANF突变体中多巴胺能神经元的存活出现与年龄相关的加速下降。通过对内质网伴侣BiP/GRP78同源物hsp-4的报告基因表达分析发现，这些动物还表现出内质网（ER）应激增加，这表明未能调节内质网未折叠蛋白反应（ER-UPR）可能是多巴胺能神经变性的一个促成因素。对hsp-4的表达研究表明，该基因广泛表达，其模式与MANF密切匹配。与hsp-4在ER-UPR中的需求一致，我们发现路易小体的主要成分α-突触核蛋白的聚集体在MANF突变动物的体壁肌肉中显著增加。总体而言，我们的工作证明了MANF在多巴胺能神经元存活和线虫内质网稳态维持中的重要作用。
