期刊论文详细信息
NEUROBIOLOGY OF DISEASE 卷:79
Effects of impaired membrane interactions on α-synuclein aggregation and neurotoxicity
Article
Ysselstein, Daniel1  Joshi, Mehul1  Mishra, Vartika1  Griggs, Amy M.1  Asiago, Josephat M.1  McCabe, George P.2  Stanciu, Lia A.3,4  Post, Carol Beth1  Rochet, Jean-Christophe1 
[1] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA
[2] Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA
[3] Purdue Univ, Sch Mat Engn, W Lafayette, IN 47907 USA
[4] Purdue Univ, Sch Biomed Engn, W Lafayette, IN 47907 USA
关键词: Aggregation;    alpha-Helix;    alpha-Synuclein;    Familial mutation;    Membrane;    Neurodegeneration;    Oligomer;    Parkinson's disease;    Phospholipid;    Vesicle;   
DOI  :  10.1016/j.nbd.2015.04.007
来源: Elsevier
PDF
【 摘 要 】

The post-mortem brains of individuals with Parkinson's disease (PD) and other synucleinopathy disorders are characterized by the presence of aggregated forms of the presynaptic protein alpha-synuclein (aSyn). Understanding the molecular mechanism of aSyn aggregation is essential for the development of neuroprotective strategies to treat these diseases. In this study, we examined how interactions between aSyn and phospholipid vesicles influence the protein's aggregation and toxicity to dopaminergic neurons. Two-dimensional NMR data revealed that two familial aSyn mutants, MOP and G51D, populated an exposed, membrane-bound conformer in which the central hydrophobic region was dissociated from the bilayer to a greater extent than in the case of wild-type aSyn. MOP and G51D had a greater propensity to undergo membrane-induced aggregation and elicited greater toxicity to primary dopaminergic neurons compared to the wild-type protein. In contrast, the non-familial aSyn mutant A29E exhibited a weak propensity to aggregate in the presence of phospholipid vesicles or to elicit neurotoxicity, despite adopting a relatively exposed membrane-bound conformation. Our findings suggest that the aggregation of exposed, membrane-bound aSyn conformers plays a key role in the protein's neurotoxicity in PD and other synucleinopathy disorders. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

Free   

【 预 览 】
附件列表
Files Size Format View
10_1016_j_nbd_2015_04_007.pdf 2382KB PDF download
  文献评价指标  
  下载次数:1次 浏览次数:0次