Autophagy in neurodegenerative disease: friend, foe or turncoat?

Autophagy, a lysosomal pathway for degrading organelles and long-lived proteins, is becoming recognized as a key adaptive response that can preclude death in stressed or diseased cells. However, during development strong induction of autophagy in specific cell populations mediates a type of programmed cell death that has distinctive ‘autophagic’ morphology and a requirement for autophagy activity. The recent identification of autophagosomes in neurons in a growing number of neurodegenerative disorders has, therefore, sparked controversy about whether these structures are contributing to neuronal cell death or protecting against it. Emerging evidence supports the view that induction of autophagy is a neuroprotective response and that inadequate or defective autophagy, rather than excessive autophagy, promotes neuronal cell death in most of these disorders. In this review, we consider possible mechanisms underlying autophagy-associated cell death and their relationship to pathways mediating apoptosis and necrosis.

Introduction

Cells stressed by injury or nutrient deprivation are often able to survive by turning over non-essential or damaged proteins and organelles to provide energy and to eliminate potentially toxic waste products. Autophagy, a regulated pathway for degrading long-lived proteins and the only pathway for turning over organelles, serves this vital function in partnership with the ubiquitin-dependent proteasome system. Obscure to many biologists a few years ago, autophagy is now being recognized as an important arbiter of death–survival decisions in cells and as a crucial defense mechanism in malignancy, infection, immune surveillance and degenerative states 1, 2, 3. Particular attention is being paid to autophagy in late-life neurodegenerative diseases, where it has been implicated in mechanisms of neurodegeneration and, in some cases, in earlier stages of disease pathogenesis [3]. Autophagic vacuoles (AVs), the general term for autophagy-related vesicular structures, have been increasingly noted in neuropathological states, but their significance to disease development is not easily interpreted. When AVs accumulate in a neuron, is the activity of autophagy increased or is the pathway blocked creating a buildup of AV intermediates behind the block? The answer to this question is crucial to resolving confusion about seemingly opposing views about the contribution autophagy makes to disease. Evidence has shown that, under adverse conditions, autophagy promotes the survival of cells, but there is also evidence that autophagy in certain pathological situations can trigger and mediate a specific form of ‘autophagic’ cell death. Are these actions of autophagy mutually exclusive in a particular diseased cell, or can they be different stages of a continuous pathological process? In cases where autophagy promotes an autophagic variant of cell death, is a distinctive pathway involved or are the more familiar cell death pathways (apoptosis or necrosis) recruited for the execution phase? These issues, as they apply to neurons in neurodegenerative states, are the subject of this article.

Chronic neurodegenerative diseases, especially in the aging brain, pose special problems for investigations of cell death pathways. Unlike neuronal cell death during development, which is relatively acute, degeneration and neuronal cell death in diseases of the aging brain reflect a struggle between pro-death disease factors and pro-survival responses that can extend over months or even years. Neurons in the final stages of their demise, therefore, often present a complex picture that defies classification as a distinct pattern of cell death. Fortunately, a growing understanding of the crosstalk between cell death pathways and experimental designs that enable a given death pathway to be genetically ablated or enhanced have begun to yield insights into the multi-faceted influence of autophagy on disease development and cell death. This review will address the physiological roles and neuroprotective actions of autophagy, and examine how either diminished or heightened autophagy activity can promote forms of cell death that have grossly similar morphologies but different mechanistic and therapeutic implications.