DNAJ Proteins in neurodegeneration: essential and protective factors.
DNAJ Proteins in neurodegeneration: essential and protective factors.
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DOI：
10.1098/rstb.2016.0534
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发表时间：
2018-01-19
期刊：
影响因子：
--
通讯作者：
Cheetham ME
中科院分区：
文献类型：
--
作者：
Zarouchlioti C;Parfitt DA;Li W;Gittings LM;Cheetham ME
蛋白质稳态的维持对于有丝分裂后细胞，特别是神经元至关重要。神经退行性疾病，如多聚谷氨酰胺扩张障碍，如亨廷顿病或脊髓小脑共济失调 (SCA)、阿尔茨海默病、额颞叶痴呆 (FTD)、肌萎缩侧索硬化症 (ALS) 和帕金森病，通常以存在聚集蛋白内含物为特征。神经元包含复杂的蛋白质网络，致力于蛋白质质量控制和维持蛋白质稳态或蛋白质稳态。分子伴侣是一类在维持蛋白质稳态方面发挥重要作用的蛋白质，其作用是结合和屏蔽新生或错误折叠蛋白质的疏水区域，同时允许正确折叠、构象变化并实现质量控制。有许多不同的分子伴侣家族在蛋白质稳态中具有多种功能。分子伴侣的 DNAJ 家族是最大的伴侣家族，由 J 结构域定义，该结构域调节 HSP70 伴侣的功能。 DNAJ 蛋白还可以具有多个其他蛋白结构域，例如泛素相互作用基序或网格蛋白结合结构域，从而在细胞中发挥多种特定作用，包括靶向客户蛋白通过蛋白酶体降解、分子伴侣介导的自噬和脱去网格蛋白包被的囊泡。 DNAJ 蛋白还可以包含 ER 信号肽或线粒体前导序列，将它们靶向细胞中的特定细胞器。在这篇综述中，我们将讨论 DNAJ 蛋白的多重作用，特别关注 DNAJ 蛋白在预防由错误折叠蛋白引起的神经退行性疾病中的作用。我们还将讨论 DNAJ 蛋白作为通过 DNAJ 家族基因突变导致遗传性神经变性的直接原因的作用。
Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders, like Huntington’s disease or spinocerebellar ataxia (SCA), Alzheimer’s disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone mediated autophagy and uncoating clathrin coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we will discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We will also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in DNAJ family genes.
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影响因子：
16.8
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作者：
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