分子伴侣HSP40/DNAJ蛋白家族及其在神经退行性疾病中的作用

分子伴侣和辅助伴侣分子能够促进新合成多肽的组装以及帮助未折叠或错误折叠的蛋白质重新折叠形成正确折叠的蛋白质，从而维持细胞内蛋白系统的稳态。作为热休克蛋白（HSP）70的辅助伴侣分子，HSP40(DNAJ)蛋白家族是目前已知的最大分子伴侣家族，能够通过J结构域与HSP70结合，从而帮助蛋白质折叠。近年研究发现，DNAJ家族蛋白与阿尔茨海默病、帕金森病、亨廷顿病、脊髓小脑性共济失调、进行性神经性腓骨肌萎缩症、脊髓性肌萎缩、远端型遗传性运动神经病变、肢带型肌营养不良、神经元蜡样质脂褐质沉积症和特发性震颤等神经退行性疾病的发生和发展有密切关系，如DNAJA1可有效降解亨廷顿蛋白聚集体；DNAJB1可降解蛋白聚集体ataxin-3;DNAJB2能够抑制亨廷顿蛋白聚集体的形成；DNAJB6能够抑制Aβ42和α-突触核蛋白的聚集；DNAJC5可以促进TDP-43、τ蛋白和α-突触核蛋白释放到细胞外空间；与特发性震颤相关的DNAJC13的突变可能阻碍核内体蛋白运输。本文就DNAJ蛋白家族在神经退行性疾病中的作用机制进行综述。

The roles of HSP40/DNAJ protein family in neurodegenerative diseases

Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ₄₂ and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space. Mutations in the essential tremor-associated DNAJC13 gene can prevent endosome protein trafficking. This article reviews the mechanism of DNAJ protein family in neurodegenerative diseases.