【摘 要】
：
Many neurodegenerative diseases are characterized by abnormal accumulations of insoluble protein aggregates, such as Amyloid beta oligomers in Alzheimer's d
【机 构】
：
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, College of Pharmaceutical S
【出 处】
：
The 7th International Symposium on Autophagy 2015(第七届自噬国际研讨会
论文部分内容阅读
Many neurodegenerative diseases are characterized by abnormal accumulations of insoluble protein aggregates, such as Amyloid beta oligomers in Alzheimer's disease and α-synuclein in Parkinson's disease.Brains in these diseases also show accumulation of autophagic vesicles in the neuron, suggesting block of the autophagic process.As lysosomal degradation is involved in all kinds of the autophagy pathway, extensive enhancement of lysosomal function is necessary.However, the involvement of lysosomal membrane proteins in autophagy and their roles in neurodegenerative diseases are not clear.Here we demonstrated that the PD-like neurodegenerative changes induced by rotenone in nigral dopamine neurons and dopaminergic cells were closely linked to a progressive decline in markers of lysosome function.We also found DNA damage-regulated autophagy modulator1 (DRAM1), an essential protein in TP53-dependent autophagy and apoptosis, was involved in this phenomenon.The rotenone-induced damage in dopamine neurons, observed in the MES 23.5 cells as well as in rat model,was reversed by overexpression DRAM1, while inhibition of DRAM1 expression by shRNA aggravated the damage induced by rotenone.Our results showed that DRAM1 afforded neuroprotection via the degradation of α-synuclein.Inhibition of autophagy activation by Bafilomycin or 3-MA blocked DRAM1-induced degradation of α-synuclein.The results provided a mechanistic link between α-synuclein toxicity and impaired DRAM1 function, supported DRAM1 as a key player in autophagy as well as against α-synuclein-induced toxicity, thus identifying DRAM1 as a promising target for therapies aimed at neuroprotection and disease modification in PD.
其他文献
The lysosomal degradation pathway, autophagy, is essential for the maintenance of cellular homeostasis.Recently, autophagy has been demonstrated to be requi
In autophagy, the unique double membrane-bound autophagosomes transiently emerge in the cytoplasm, sequester portion of the cytosol and organelles, and eventual
Platycodin D (PD) is the main saponin isolated from the traditional Chinese herb Platycodon radix.It exhibits anticancer activity in several types of cancer
Unc-51-like kinases (ULKs) are the most upstream kinases in the initiation of autophagy, yet the molecular mechanisms underlying their function in this key
Receptor-mediated mitophagy plays a fundamental role in selectively removing damaged or unwanted mitochondria.We have recently identified that FUNDC1 is a novel
Autophagy is a process of self-cannibalization at the cellular level which involves sequestration of cytosolic components within a double membranous structu
Xenophagy is specific autophagic process by which a cell defends against pathogens such as bacteria and viruses.The NDP52 related to xenophagy is one of sev
The budding yeast has only one class Ⅲ PI3-kinase, Vps34, which specifically phosphorylates position-3 of phosphatidylinositol.The product, phosphatidylino
Autophagy is a major catabolic pathway for maintaining cell homeostasis through degradation and recycle of macromolecules and organelles.Autophagy can be ac
Mutations in the PINK1 and PARK2 genes are associated with Parkinson's disease, and the corresponding proteins Pink1 and Parkin are critical in the removal