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Abstract
Macroautophagy is a highly regulated intracellular process that, under certain circumstances, delivers cytoplasmic components to the lysosomes for degradation. It consists of several sequential steps including initiation and nucleation, double membrane formation and elongation, formation and maturation of autophagosomes and finally autophagosomes/lysosomes fusion and degradation of intra-autophagosomal contents by lysosomal enzymes. After decades of considering autophagy as a cell death pathway, it has recently been shown to have a survival function through clearing of protein aggregates and damaged cytoplasmic organelles in response to a variety of stress conditions. Most recently, there is increasing evidence from literature revealing that autophagy induction may combat neurodegeneration. In the light of this, our current review tried to address the recent advances in the role of induced autophagy in neuroprotection with a particular focus on its contribution in the most common neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
Acknowledgements
The authors wish to thank G Gille, Department of Neurology, Technical University Dresden, Germany for proofreading of this manuscript.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Autophagy is one of the major breakdown systems in eukaryotic cells that aims to sequester unnecessary materials and dysfunctional organelles into lysosomes for degradation.
Three levels of autophagy occur in eukaryotic cells including basal, upregulated and induced autophagy.
Basal autophagy occurs in most eukaryotic cells and plays a critical role in maintaining cellular homeostasis and genomic integrity during embryogenesis, and pre-natal and post-natal developmental stages by selectively removing misfolded and aggregate-prone proteins, and damaged organelles.
In response to stress, autophagy is upregulated and constitutes a stress adaptation pathway to promote cell survival.
Induction of autophagy over the basal or upregulated levels appears to be beneficial in a number of human diseases.
Most recently, autophagy alterations have been linked to neuronal death in neurodegenerative diseases and at the same time, autophagy modulation has been shown to be a promising therapeutic intervention in in vitro and in vivo models of some neurodegenerative diseases.
In Alzheimer’s disease, autophagy alterations were reported to result in drastic inhibition of β-amyloid (Aβ) secretion leading to aberrant Aβ accumulation and subsequent cell death.
Rapamycin, a well-documented autophagy inducer, was shown to reduce Aβ accumulation and to attenuate tau hyperphoshorylation in in vitro and in vivo models of Alzheimer’s disease through inhibition of the mTOR.
As well, autophagy dysfunction has been implicated as an important issue in Parkinson’s disease (PD) pathogenesis as it results in accumulation of damaged mitochondria and α-synuclein, the two important factors mediating cell death in PD.
Autophagy inducers, most notably rapamycin and resveratrol, have been reported to protect in vitro and in vivo PD models through facilitating the clearance of damaged mitochondria and degradation of α-synuclein by autophagy activation.
In Huntington’s disease (HD), clearance of mutant huntingtin was reported to depend greatly on autophagy, and data from HD experimental models and HD brains suggest a significant role for autophagy dysfunction in HD pathogenesis.
Rapamycin was shown to reduce the levels of aggregate-prone proteins and the cell death associated with polyglutamine and polyalanine expansions in cellular HD models.
Recent advances in the understanding of the molecular processes contributing to autophagy have shown a tight connection between autophagy and apoptosis.
Atg5, Atg12 and Beclin-1 are important autophagy proteins that are involved in regulation of apoptotic pathway.
Bcl-2, FLIP and caspases are best reported examples of the apoptotic proteins that regulate autophagic process.