Autophagy in the Central Nervous System: Implications for Neurodegenerative Disorders

Maria      Xilouri; Leonidas      Stefanis

doi:10.2174/187152710793237421

Abstract

The autophagy-lysosomal pathway is a major proteolytic pathway that in mammalian systems mainly comprises of macroautophagy and chaperone-mediated autophagy. The former is relatively non-selective and involves bulk degradation of proteins and organelles, whereas the latter is selective for certain cytosolic proteins. These autophagy pathways are important in development, differentiation, cellular remodeling and survival during nutrient starvation. Autophagy is crucial for neuronal homeostasis and acts as a local housekeeping process, since neurons are post-mitotic cells and require effective protein degradation to prevent accumulation of toxic aggregates. A growing body of evidence now suggests that dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles. Such accumulation has been linked to synaptic dysfunction, cellular stress and neuronal death. Abnormal autophagy may be involved in the pathology of both chronic nervous system disorders, such as proteinopathies (Alzheimers, Parkinsons, Huntingtons disease) and acute brain injuries. Although autophagy is generally beneficial, its aberrant activation may also exert a detrimental role in neurological diseases depending on the environment and the insult, leading to autophagic neuronal death. In this review we summarize the current knowledge regarding the role of autophagy-lysosomal pathway in the central nervous system and discuss the implication of autophagy dysregulation in human neurological diseases and animal models.

Keywords: Autophagosome, chaperone-mediated autophagy, LAMP-2A receptor, LC3, macroautophagy, neurodegenerative diseases, autophagy-lysosomal pathway, Parkinson's disease, Lewy body dementias, Alzheimer's disease, Huntington's disease, Prion Diseases, Frontotemporal dementias, Amyotrophic lateral sclerosis, microautophagy, pexophagy, reticulophagy, ER-phagy, rapamycin, mTOR, autophagolysosomes, amphisomes, Atg14L, Rubicon, UVRAG, MAP1LC3, ESCRT, LAMP-2A, HDAC6, Ambra1, CHMP4B, neuronal ceroid lipofuscinosis, Batten disease, C elegans, metamphetamine-induced injury, KFERQ, ASYN gene, MEF2D, Bafilomycin, SMER, amyloidogenesis, polyQ diseseases, spinobulbar muscular atrophy, dentatorubral, pallidoluysian atrophy, temsirolimus, Scrg1, Creutzfeldt-Jakob disease, NIEMANN-PICK C DISEASE