Dysregulation of protein trafficking in neurodegeneration

Molecular Neurodegeneration

Huaxi Xu¹  Guojun Bu²  Timothy Huang¹  Xin Wang¹ 

[1] Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China

关键词: Endocytic trafficking;    Parkinson’s disease;    Down syndrome;    Alzheimer’s disease;    Ras-related GTP-binding protein;    The retromer complex;    Sorting nexin;    γ-secretase;    β-secretase;    β-amyloid precursor protein;   

Others  :  1138751
DOI  :  10.1186/1750-1326-9-31

 received in 2014-07-29, accepted in 2014-08-14,  发布年份 2014

【 摘 要 】

Intracellular protein trafficking plays an important role in neuronal function and survival. Protein misfolding is a common theme found in many neurodegenerative diseases, and intracellular trafficking machinery contributes to the pathological accumulation and clearance of misfolded proteins. Although neurodegenerative diseases exhibit distinct pathological features, abnormal endocytic trafficking is apparent in several neurodegenerative diseases, such as Alzheimer’s disease (AD), Down syndrome (DS) and Parkinson’s disease (PD). In this review, we will focus on protein sorting defects in three major neurodegenerative diseases, including AD, DS and PD. An important pathological feature of AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of β-amyloid (Aβ) peptide aggregates. Multiple lines of evidence demonstrate that over-production/aggregation of Aβ in the brain is a primary cause of AD and attenuation of Aβ generation has become a topic of extreme interest in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavage by β-secretase and the γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα which precludes Aβ generation. DS patients display a strikingly similar pathology to AD patients, including the generation of neuronal amyloid plaques. Moreover, all DS patients develop an AD-like neuropathology by their 40 s. Therefore, understanding the metabolism/processing of APP and how these underlying mechanisms may be pathologically compromised is crucial for future AD and DS therapeutic strategies. Evidence accumulated thus far reveals that synaptic vesicle regulation, endocytic trafficking, and lysosome-mediated autophagy are involved in increased susceptibility to PD. Here we review current knowledge of endosomal trafficking regulation in AD, DS and PD.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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