Abstract
Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases.
Highlights
Neurons have highly specialized structures for intercellular communication, which typically include the axon, dendrites and synapses (Figure 1)
As beclin 1 expression decreases in an age-dependent fashion in the human brains and the heterozygous deletion of beclin 1 gene is insufficient for the regulation of autophagosomes, it has been proposed that the age-dependent decrease of beclin 1 expression may lead to a reduction of autophagic activity, which in turn promotes the accumulation of mutant Htt and the progression of the disease (Shibata et al, 2006)
Neuronal integrity is more sensitive to alterations in basal autophagy than that of non-neuronal cells due to their postmitotic nature and the specialized structures necessary for intercellular communications
Summary
Neurons have highly specialized structures for intercellular communication, which typically include the axon, dendrites and synapses (Figure 1). These observations collectively suggest that autophagy plays a critical role in the pathogenesis of AD and that the inhibition of mTOR signaling and/or the activation of beclin 1 signaling may reduce Aβ and tau pathology, subsequently improving learning and memory in AD patients.
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