The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases - PubMed (original) (raw)

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The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases

Zhenyu Yue et al. Biochim Biophys Acta. 2009 Sep.

Abstract

Autophagy is a tightly regulated cell self-eating process. It has been shown to be associated with various neuropathological conditions and therefore, traditionally known as a stress-induced process. Recent studies, however, reveal that autophagy is constitutively active in healthy neurons. Neurons are highly specialized, post-mitotic cells that are typically composed of a soma (cell body), a dendritic tree, and an axon. Despite the vast growth of our current knowledge of autophagy, the detailed process in such a highly differentiated cell type remains elusive. Current evidence strongly suggests that autophagy is uniquely regulated in neurons and is also highly adapted to local physiology in the axons. In addition, the molecular mechanism for basal autophagy in neurons may be significantly divergent from "classical" induced autophagy. A considerable number of studies have increasingly shown an important role for autophagy in neurodegenerative diseases and have explored autophagy as a potential drug target. Thus, understanding the neuronal autophagy process will ultimately aid in drug target identification and rational design of drug screening to combat neurodegenerative diseases.

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Figures

Figure 1

Figure 1

A schematic representation of the macroautophagy process. Following induction, a phagophore or isolation membrane is formed. This process is regulated by Atg1 (Ulk1), Atg9, and the PtdIns 3-kinase complex, which includes Beclin 1, Atg14L, and UVRAG (nucleation). Two ubiquitin-like conjugation systems, which produce Atg8-PE (LC3II) and Atg5-Atg12, mediate the elongation of the isolation membrane, closure, and the formation a double-membrane vacuole known as the autophagosome. Autophagosomes can undergo maturation and fusion with early and late endosomes and MVBs, to generate the amphisome, followed by fusion with lysosomes, to form the autolysosome. Trafficking, maturation, and fusion events are mediated by microtubules and specific SNARE and Rab proteins. ESCRT proteins are also essential for MVB fusion with autophagosomes. Alternatively, immature autophagosomes can fuse directly with lysosomes.

Figure 2

Figure 2

Proposed model for neuronal autophagy in the axons. Under normal conditions, basal autophagy maintains axonal homeostasis by removal of “autophagic cargo” (top). The “autophagic cargo” undergoes retrograde axonal transport to the soma and fuses with lysosomes for degradation. Stress or injury can induce local biosynthesis of autophagosomes, resulting in their accumulation in axons and axon terminals. It has been suggested that, under pathological conditions, precursors of degradative vesicles or lysosomes may be anterogradely transported to the axon terminal and contribute to the degradation of autophagosomes (bottom left). Neurons deficient in autophagy amass proteins, organelles, and aberrant membrane structures at axon terminals, resulting in gross axonal swellings or dystrophy (bottom right).

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References

    1. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007;9:1102–1109. - PubMed
    1. Novikoff AB. Electron microscopy: cytology of cell fractions. Science. 1956;124:969–972. - PubMed
    1. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–492. - PubMed
    1. Dixon JS. “Phagocytic” lysosomes in chromatolytic neurones. Nature. 1967;215:657–658. - PubMed
    1. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L, Tolkovsky A. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005;1:11–22. - PubMed

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