Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications

Autophagy is a highly conserved intracellular pathway involved in the elimination of proteins and organelles by lysosomes. Known originally as an adaptive response to nutrient deprivation in mitotic cells, autophagy is now recognized as an arbiter of neuronal survival and death decisions in neurodegenerative diseases. Studies using postmortem human tissue, genetic and toxin-induced animal and cellular models indicate that many of the etiological factors associated with neurodegenerative disorders can perturb the autophagy process. Emerging data support the view that dysregulation of autophagy might play a critical role in the pathogenesis of neurodegenerative disorders. In this review, we highlight the pathophysiological roles of autophagy and its potential therapeutic implications in debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer's, Parkinson's and Huntington's diseases.

Introduction

Autophagy or self-eating is a lysosome-mediated degradation process for non-essential or damaged cellular constituents. It plays an important homeostatic role in cells and preserves the balance between synthesis, degradation and subsequent recycling of cellular components [1]. During autophagy, cytoplasmic constituents (including misfolded or aggregated proteins), damaged organelles [such as mitochondria, endoplasmic reticulum (ER) and peroxisomes], and intracellular pathogens are sequestered into double-membrane autophagosomes and their contents are then degraded by lysosomal hydrolases. This machinery has been implicated in multiple physiological processes, including protein and organelle turnover, stress response, cellular differentiation and programmed cell death, in addition to various pathological settings [2]. Whereas basal levels of autophagy ensure the physiological turnover of old and damaged organelles as a garbage removal process, it is thought that significant accumulation of autophagosomes is either an alternative pathway of cell death or an ultimate cellular survival attempt in response to stress [3].

It has recently been observed that autophagosomes are abundant in neurons in an increasing number of neurodegenerative disorders. Such observations have provoked controversial viewpoints about whether these structures foster neuronal cell death or render neuroprotection. It is often debated whether autophagosome accumulation in neurons leads to an increase in autophagic activity or rather is a consequence of impaired autophagic degradation leading to a buildup of autophagosomes. Whether autophagy induction in neurons leads to cell death (traditionally mediated via conserved canonical pathways such as apoptosis and necrosis [4]) or simply occurs as a process alongside these other pathways is a controversial issue. Thus, it is crucial to address these opposing views in defining its fundamental role in neuronal physiology [5].

It is becoming increasingly evident that autophagy can contribute differently to cell death induction according to the type and degree of environmental changes or stress stimuli. Cell response might gradually shift from elimination of damaged proteins and organelles via autophagy, which leads to its recovery, to the induction of apoptotic pathways determining cellular demise. However, in the context of neurodegenerative disorders, an emerging consensus is 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 [6]. In this review, we provide an overview of current understanding of the putative role of autophagy mechanisms in common neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Furthermore, we discuss how current knowledge about this degradation machinery could be harnessed to design potential therapeutic approaches.