Autophagy for tissue homeostasis and neuroprotection
Introduction
Autophagy (from the Greek, ‘auto’: oneself and ‘phagy’: to eat) refers to any cellular degradative pathway that involves the delivery of cytoplasmic cargo to the lysosome [1, 2, 3, 4•]. The autophagic degradation routes can be classified into at least three different pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy [5, 6, 7]. Macroautophagy is the major lysosomal pathway for the turnover of cytoplasmic components and will hereafter be referred to as ‘autophagy’. This process begins with the engulfment of cytoplasmic constituents by a membrane sac, called the isolation membrane or phagophore. Then, this structure forms a double-membrane vesicle, called the autophagosome, which contains bulk — or specifically selected — portions of cytoplasm [2, 8]. Once their formation is complete, autophagosomes eventually fuse with lysosomes and acquire hydrolytic activity. Finally, the autophagic cargo is degraded and the resulting essential biomolecules are recycled back to the cytoplasm to satisfy the anabolic and energetic requirements of the cell [7]. Autophagic activity can be enhanced in response to a wide variety of intracellular and extracellular stimuli and represents an essential mechanism by which organisms can adapt to acute stress conditions, especially to starvation [2, 4•, 9, 10, 11]. However, in virtually all nucleated cells, autophagy is constitutively active at low basal levels to perform homeostatic functions such as protein and organelle turnover. In fact, constitutive autophagy has acquired a growing relevance in the homeostasis of higher eukaryotes, at multiple levels. In this review, we will briefly describe the homeostatic functions of the autophagic pathway in the context of different tissues as they have been elucidated in animal models of tissue-specific autophagy deficiency. We will lay special emphasis on autophagy in the central nervous system (CNS), given its growing relevance as a potential clinical target for the treatment of CNS-related pathologies. This may influence the treatment of a variety of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), and Huntington, Parkinson or Alzheimer diseases [12, 13•, 14, 15].
Section snippets
Autophagy, a degradative pathway essential for tissue homeostasis
In the last decade, the detailed molecular characterization of macroautophagy and the development of methods to monitor and manipulate autophagic activity in both in vitro systems and in experimental animal models have yielded spectacular advances in the understanding of the molecular basis, regulation, and roles of autophagy. In fact, the autophagic pathway has emerged as an essential component to maintain cellular and tissue homeostasis. The whole-body knockout of essential autophagy genes is
The protective role of autophagy in the CNS
Although neuronal autophagy is substantially reduced as compared to that found in other cellular types under conditions of acute starvation [4•], the integrity of the CNS is more dependent on basal autophagy than that of other tissues. In the CNS, cellular division is mostly limited to developmental stages, and mature neurons have a limited or null potential of proliferation, meaning that damaged organelles and misfolded proteins cannot be redistributed among daughter cells and inexorably
Autophagy in neurodegeneration: friend or foe?
Given the major homeostatic roles of autophagy in neuronal cells, it seems logical that alterations in autophagic activity are commonly associated with degenerative CNS disorders (Figure 1). However, the nature of this relationship is complex and nonunivocal, as the accumulation of autophagosomes (detected by transmission electron microscopy or immunohistochemistry) may result either from an increase in autophagic sequestration or from a blockade in autophagic flux. Hence accumulation of
Autophagy induction for the avoidance of neurodegeneration
There is mounting evidence that pharmacological stimulation of autophagic flux constitutes a promising clinical strategy for the treatment of neurodegenerative disorders. In fact, it has been reported that treatment with rapamycin or its analogues, the ‘rapalogues’, which all enhance autophagosome formation through the inhibition of mTORC1, protects against the toxicity of a wide variety of aggregate-prone proteins in vitro (including those associated with HD, SCAs, PD, or FTD) and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
GK is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Apo-Sys, ChemoRes), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa), Cancéropôle Ile-de-France and AXA Chair for longevity research. GM receives a fellowship from EMBO. FM is supported by the Fonds zur Foerderung der Wissenschaftlichen Forschung.
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