Review: autophagy and neurodegeneration: survival at a cost?

Abstract

Protein aggregation, mitochondrial impairment and oxidative stress are common to multiple neurodegenerative diseases. Homeostasis is regulated by a balanced set of anabolic and catabolic responses, which govern removal and repair of damaged proteins and organelles. Macroautophagy is an evolutionarily conserved pathway for the degradation of long-lived proteins, effete organelles and protein aggregates. Aberrations in macroautophagy have been observed in Alzheimer, Huntington, Parkinson, motor neuron and prion diseases. In this review, we will discuss the divergent roles of macroautophagy in neurodegenerative diseases and suggest a potential regulatory mechanism that could determine cell death or survival outcomes. We also highlight emerging data on neurite morphology and synaptic remodelling that indicate the possibility of detrimental functional trade-offs in the face of neuronal cell survival, particularly if the need for elevated macroautophagy is sustained.

Figure 1

Autophagy reduces neuronal protein aggregates. Aggregate-prone proteins and oligomers, such as amyloid-beta, prions, huntingtin, alpha-synuclein and tau, are engulfed by autophagosomes. After sequestration, autophagosomes deliver the aggregates/preaggregates to the lysosome for degradation. Autophagic clearance thus prevents deposition of further aggregates, inhibiting the formation of histologically visible plaques and intracellular aggregates. Amyloid-beta and alpha-synuclein have each been shown to reduce the efficiency of lysosomal degradation, potentially contributing to an amplifying cycle for further accumulation of protein aggregates. Similarly normal ageing may also involve a decline in lysosomal efficiency.

Figure 2

PINK1 deficiency induces PI3K/Beclin 1-dependent autophagy. (A) PI3K inhibitors, 3-methyladenine (3MA) or wortmannin (WTN), reduce the number of GFP-LC3-labelled autophagic vacuoles (puncta) induced by PINK1 knock-down in two SH-SY5Y clones, A14 and D14, as compared with V17 vector stable cells (*P < 0.05 vs. vector stable control line; †P < 0.05 vs. respective untreated PINK1 shRNA line; mean ± SE). (B) RNAi using a previously described protocol for human Beclin 1 [6] also reduces the number of GFP-LC3 puncta in PINK1-deficient cells (*P < 0.05 vs. vector stable control line; †P < 0.05 vs. scrambled control siRNA in the respective stable line; mean ± SE).

Figure 3

Canonical vs. non-canonical autophagy? In different model systems, induction of autophagy results in divergent outcomes. For example, nitrogen starvation, trophic factor withdrawal, PINK1 deficiency or aggregopathies each induce autophagy that is neuroprotective. However, autophagy appears to contribute to MPP+, resveratrol, hypoxic/ischaemic and p53 up-regulated modifier of apoptosis (PUMA)-dependent cell death. Interestingly, non-canonical autophagy that does not require Beclin 1 has only been reported in a small number of systems, but in each of these, autophagy plays a detrimental role, promoting cell death or neurite retraction. Given that competition for limiting amounts of Beclin 1 has been proposed as a means by which Bcl2 suppresses autophagy [49], we hypothesize that mechanisms that bypass the requirement for Beclin 1 may determine whether or not autophagy is induced to a pro-death level. The role of autophagy is further complicated by considerations of neuronal functional capacity. RNAi studies indicate that Atg7- and LC3-dependent autophagy contributes to the shortening of neurites in both Beclin 1-dependent and independent contexts. While the long-term functional consequences of this remain uncharacterized, it is possible that neuronal survival is enhanced by retraction of neurites, but at a cost to the neural network, contributing to circuit dysfunction in neurodegenerative diseases. Thus, the potential physiologic role(s) of autophagy in neuronal function and plasticity, as well as the functional consequences of autophagy induced in response to pathologic stresses, remain as critically important areas for future investigation.