Journal of Molecular Biology
ReviewAutophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases
Graphical abstract
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.
Section snippets
Alzheimer’s Disease and Tauopathies
AD is a neurodegenerative disease clinically characterized by progressive dementia and cognitive impairment. The pathology of AD is defined by the presence of two main hallmark elements: intracellular accumulation of neurofibrillary tangles (formed of hyperphosphorylated tau, a microtubule-associated protein) and extracellular deposits of amyloid-β (Aβ) plaques arising from defective amyloid precursor protein (APP) processing. AD is the most common of the tauopathies, a class of
Parkinson’s Disease
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder primarily characterized by progressive loss of motor control, and in many cases, cognitive decline. These symptoms are the result of the death of dopaminergic neurons in the substantia nigra pars compacta, and are associated with the accumulation of intraneuronal protein aggregates (Lewy bodies), predominantly comprised of α-synuclein (α-syn) [80]. A large body of evidence implicates defective autophagy as central to both the
Polyglutamine Diseases
There are currently nine known diseases caused by polyglutamine expansion mutations: Huntington’s disease (HD); spinal and bulbar muscular atrophy (SBMA); dentatorubropallidoluysian atrophy (DRPLA); and spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 [144]. These mutations are encoded by the expansion of a (CAG)n trinucleotide repeat tract in the relevant proteins. For example, in HD, up to 35 CAGs are well-tolerated and considered within the range of normal variation, while 36 or more
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is characterized by progressive degeneration of upper and lower motor neurons. The majority (~90%) of ALS cases are sporadic, and only 5–10% of all cases have been reported to be familial [183]. A large number of pathogenic mutations within over 30 genes have been linked to ALS. The most commonly involved genes are superoxide dismutase (SOD1) [184], fused in sarcoma (FUS) [185], TAR DNA-binding protein 43 (TDP-43) [
Conclusion and Perspective
Deficits in protein homeostasis are a shared mechanism across neurodegenerative diseases, and therefore increasing protein clearance via autophagy is an attractive strategy that may be applicable in multiple diseases. As described above, evidence in disease models indeed demonstrates promising results in many cases, with autophagy upregulation being able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression in a number of models.
Effectively utilizing
Acknowledgements
We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), Roger de Spoelberch Foundation, Alzheimer’s Research UK, The Tau Consortium, Cambridge Centre for Parkinson-Plus, National Institute for Health Research Cambridge Biomedical Research Centre (D.C.R.), Cambridge Commonwealth, European & International Trust (to AD, SK, and RP); Romanian grant of Ministry of Research and Innovation CNCS –UEFISCDI, project
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Joint first authors.