Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

Highlights

• Autophagy delivers cytoplasmic cargoes to lysosomes for degradation.

• It degrades many aggregate-prone proteins responsible for neurodegenerative disease.

• Enhancing autophagy has therapeutic potential in common neurodegenerative diseases.

• Evidence in cells and in vivo demonstrates promising results in many disease models.

• Outcomes may depend on how autophagy impacts disease pathogenesis.

Abstract

Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may contribute to pathology in some cases. Autophagy degrades many of the toxic, aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others, raising the possibility that autophagy upregulation may help to reduce levels of toxic protein species, and thereby alleviate disease. This review examines autophagy induction as a potential therapy in several neurodegenerative diseases—Alzheimer’s disease, Parkinson’s disease, polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Evidence in cells and in vivo demonstrates promising results in many disease models, in which autophagy upregulation is able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression. However, the effective therapeutic use of autophagy induction requires detailed knowledge of how the disease affects the autophagy-lysosome pathway, as activating autophagy when the pathway cannot go to completion (e.g., when lysosomal degradation is impaired) may instead exacerbate disease in some cases. Investigating the interactions between autophagy and disease pathogenesis is thus a critical area for further research.

Introduction

Macroautophagy (henceforth referred to as autophagy) is a major, conserved cellular process by which cells deliver cytoplasmic contents to lysosomes for degradation. This transport involves the delivery of these contents by double-membraned vesicles called autophagosomes, in contrast with other pathways, like chaperone-mediated autophagy (CMA) and microautophagy, which do not involve vesicular transport. While autophagy was initially characterized as a primordial, nonselective degradation pathway induced to counteract nutrient deprivation, it has become increasingly clear that autophagy plays a key role in the homeostasis of nonstarved cells. Critically, autophagy appears to degrade aggregate-prone proteins, damaged mitochondria, and invading pathogens, and these functions appear to be linked to a range of human diseases [1,2].

One area of particular interest is the relevance of autophagy to neurodegenerative diseases. Many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, manifest with the accumulation of oligomers and aggregates of misfolded proteins. As these proteins exert toxic effects on cells, lowering the levels of these proteins can be therapeutically favorable [1]. Autophagy degrades many of the toxic aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others [[3], [4], [5]]. Many of these proteins also cause disruptions in autophagy [6,7], raising the possibility that their ability to hinder autophagy contributes to their toxicity. In further support of a relationship between autophagy and neurodegenerative disease, some risk genes linked to neurodegenerative diseases play a role in the autophagy pathway [1,8]. This considerable body of evidence linking autophagy and neurodegeneration gives rise to the possibility that autophagy upregulation may be a viable therapeutic strategy in some neurodegenerative diseases.

Understanding the interplay between autophagy and neurodegeneration requires a knowledge of the multiple steps and regulatory pathways involved in the autophagy pathway (Fig. 1). The process of autophagy involves a series of regulated mechanical steps, including autophagosome formation, maturation, and closure [2,9]. The initial stages of autophagy are marked by cup-shaped, double-membraned phagophores, the formation of which requires PI(3)P generation by the Beclin-1-VPS34 complex [10,11]. The edges of these phagophores subsequently extend and fuse to form autophagosomes [12]. These are trafficked towards the proximity of lysosomes via the dynein machinery on microtubules [13], which allows fusion with lysosomes and degradation of autophagosomal contents. Each of these steps is subject to regulation by various upstream signaling pathways, notably via mTORC1, a major regulator of cell metabolism [14], and TFEB [15], a key transcriptional regulator of autophagy and lysosomal biogenesis. Autophagic flux, thus, depends on multiple steps and requires coordination between autophagosome biogenesis and lysosomal degradation. Interventions aimed at inducing autophagy have been targeted towards various stages in this process, potentially leading to different effects on disease progression (see Table 1).

This review will focus primarily on the potential of autophagy upregulation as a therapeutic strategy in several classes of neurodegenerative disease: Alzheimer’s disease (AD) and tauopathies, Parkinson’s disease (PD), polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Although most instances of neurodegenerative disease are sporadic, a small number of cases in each disease have been associated with disease-causing mutations in critical genes (Fig. 1). These cases have allowed for the generation of important insights into the pathogenesis of each disease and are used in many of the cell and animal models of each illness. In each section, we briefly explore how proteins linked to the relevant disease impact autophagy. Subsequently, we describe the evidence in cells and in vivo models on whether autophagy induction may be of therapeutic value. Thorough reviews have previously been published on the pathogenesis of each of the described neurodegenerative diseases [[16], [17], [18], [19]] and on the cell biology of autophagy [1,2], so these will not be explored in detail here.