Autophagy in axonal and dendritic degeneration

Abstract

Degeneration of axons and dendrites is a common and early pathological feature of many neurodegenerative disorders, and is thought to be regulated by mechanisms distinct from those determining death of the cell body. The unique structures of axons and dendrites (collectively neurites) may cause them to be particularly vulnerable to the accumulation of protein aggregates and damaged organelles. Autophagy is a catabolic mechanism in which cells clear protein aggregates and damaged organelles. Basal autophagy occurs continuously as a housekeeping function, and can be acutely expanded in response to stress or injury. Emerging evidence shows that insufficient or excessive autophagy contributes to neuritic degeneration. Here, we review the recent progress that has begun to reveal the role of autophagy in neurite function and degeneration.

Figure 1

Biogenesis, maturation and dynamic transport of autophagosomes and autolysosomes in healthy and degenerating axons. (a) Under normal conditions, autophagosomes may arise in the distal ends of healthy axons, become acidified (matured), and initiate retrograde transport along axons depending on microtubules and dynein/dynactin complex. Mature autophagosomes (autolysosomes) switch to bidirectional motility and initiate the proteolytic clearance of the autophagy substrates. (b) Upon certain insults, autophagosomes are induced in a large number, exceeding the rate of clearance. As result, autophagosomes/autolysosomes accumulate in axonal swellings or beadings associated with protein aggregates and collapsed cytoskeleton.

Figure 2

Link of autophagy and diverse neuritic degenerative features. Autophagic process may be involved in a variety of neuritic degenerative features, including terminal degeneration (a), neuritic retraction (a), synaptic dysfunction (b) and neuritic swelling (c). APP, amyloid precursor protein.

Figure 3

Putative molecular pathways involved in autophagy-associated neuritic degeneration. Although the underlying mechanism of autophagy-associated neuritic degeneration is still elusive, several pathways might contribute to this process: (i) Autophagy acts as a downstream target of calcium influx following mechanical axonal damage. Calpain may block autophagy activation by mediating the cleavage of Atg5. (ii) MEK/ERK may act as upstream signals of autophagic induction. (iii) Several molecules, including NIX, PINK1 and parkin, may participate in mitophagy. (iv) Autophagy may also mediate the clearance of cleaved caspase-3, reflecting the cross-talk between autophagy and apoptosis in the execution of cell death. (v) Moderate autophagic activation may contribute to neuritic survival, while insufficient or overactivated autophagy lead to neuritic degeneration. ERK, extracellular signal regulated protein kinase; LC3, microtubule-associated protein light chain 3; MEK, mitogen activated protein kinase/ERK kinase; NIX, NIP3-like protein X; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase 1.