Acta Pharmacologica Sinica (2013) 34: 600–604; doi: 10.1038/aps.2012.189; published online 4 Feb 2013

 Abstract

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and amyotropic lateral sclerosis.

Introduction to autophagy

Macroautophagy (which we will call autophagy) is initiated by the formation of a cup-shaped double-membrane structure (the phagophore) in the cytoplasm. The origin of this structure is still under investigation, but currently the endoplasmic reticulum, Golgi, mitochondria and the plasma membrane are all proposed to be potential sources (which may not be mutually exclusive)1,2,3. The phagophore edges expand and then seal to engulf intracytoplasmic cargo, such as protein oligomers, organelles and ribosomes, thereby sequestering the cargo in a double-membrane called an autophagosome. Autophagosomes are then trafficked along microtubules towards the microtubule-organizing centre, where they mature through fusion with multivesicular bodies and early and/or late endosomes, before fusing with lysosomes. The autophagosomal contents are then degraded by lysosomal hydrolases and the degradation products are then transported back into the cytoplasm to be recycled.

It has been well established that autophagy regulates important biological functions, such as cell survival, cell death, cell metabolism, development, aging, infection and immunity. At a cellular level, the involvement of autophagy in the cell death and cell survival processes appears to be complex. The visualization of autophagosomes in dying cells has led certain groups to conclude that autophagy can serve as a nonapoptotic form of programmed cell death4. Although cells can manifest a clear increase in the numbers of autophagosomes shortly before or during their death, this phenomenon is sometimes due to defects in autophagosomal maturation and, hence, decreased, rather than increased, autophagy5,6. Most evidence indicates that autophagy is primarily a pro-survival rather than a pro-death mechanism, and in the context of neurodegenerative disorders, an emerging consensus is that induction of autophagy is a neuroprotective response and that defective autophagy promotes pathology.

Autophagy malfunction and neurodegenerative diseases

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer Disease (AD), Huntington's Disease (HD), Parkinson's Disease (PD) and Amyotropic Lateral Sclerosis (ALS).

http://www.nature.com/aps/journal/v34/n5/full/aps2012189a.html