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 beta-amyloid (Abeta) peptide aggregates.
Multiple lines of evidence demonstrate that over-production/aggregation of Abeta in the brain is a primary cause of AD and attenuation of Abeta generation has become a topic of extreme interest in AD research. Abeta is generated from beta-amyloid precursor protein (APP) through sequential cleavage by beta-secretase and the gamma-secretase complex.
Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain to release soluble APPalpha which precludes Abeta 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 40s. 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.
Author: Xin WangTimothy HuangGuojun BuHuaxi Xu
Credits/Source: Molecular Neurodegeneration 2014, 9:31
Published on: 2014-08-25
Tweet
News Provider: 7thSpace Interactive / EUPB Press Office
Social Bookmarking
RETWEET This! | Digg this! | Post to del.icio.us | Post to Furl | Add to Netscape | Add to Yahoo! | Rojo
There are no comments available. Be the first to write a comment.