ABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear. RESULTS: We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology. CONCLUSIONS: In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.
Subject(s)
Alzheimer Disease , HSP40 Heat-Shock Proteins , Molecular Chaperones , Nerve Tissue Proteins , Neuroblastoma , Animals , Humans , Mice , Alternative Splicing , Alzheimer Disease/genetics , HSP40 Heat-Shock Proteins/genetics , HSP40 Heat-Shock Proteins/chemistry , HSP40 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/genetics , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Nerve Tissue Proteins/genetics , Protein Folding , Protein Isoforms/genetics , Protein Isoforms/metabolismABSTRACT
BACKGROUND: Increasing attention is being given to the use of Chinese medicine (CM) for preventing and healing vascular complications of chronic ulcerative lesions of diabetic foot. OBJECTIVES: The purposes of this paper are to describe some benefits of CM for the treatment of diabetic foot and to provide some expert opinions based on some case studies and evidence from documented Chinese traditional medicine literature. METHODS: A critical review of the literature and a case report. RESULTS: Cumulative evidence in the literature indicate that CM preparations possess anti-inflammatory activities, antioxygenation, antibiosis, antibacterial, antiallergic and beneficial effect on the viability of fibroblasts. Case record suggested that after CM treatment the patient with Wagner Grade IV ulcers healed completely. CONCLUSION: It is becoming increasingly important for integrated CM and biomedicine therapy to treat diabetes-related vascular complications. The opportunities for effective CM interventions are significant, and more solid evidence is warranted to show the efficacy of CM in the treatment of diabetic foot ulcers in the near future.