In search of new targets for retinal neuroprotection: is there a role for autophagy?
Graphical abstract
Highlights
► Autophagy is a catabolic process essential for neuronal survival. ► Autophagy dysfunction has been implicated in neurodegeneration. ► Autophagy deregulation has been reported in RGCs exposed to detrimental stimuli. ► Modulation of autophagy represents a promising approach to neuroprotection.
Introduction
Retinal ganglion cell (RGC) death is the common final event of several retinopathies and optic neuropathies, including glaucoma. The term glaucoma indicates an etiologically heterogeneous, but clinically similar, group of optic neuropathies characterized by progressive deterioration of the visual field owing to the death of RGCs and degeneration of the optic nerve [1].
As for many other neurodegenerative pathologies, the cellular and molecular pathophysiology of glaucoma is poorly understood, reflecting its complex and multifactorial etiology.
Elevated intraocular pressure (IOP) has been considered, along with advanced age, the main (and, to date, the only therapeutically modifiable) risk factor associated with the onset and the progression of the neuropathy [2]. Nevertheless, an elevated IOP is neither necessary nor sufficient for the onset or progression of the disease; in fact, patients can continue to lose vision also when IOP is successfully controlled [3]. Therefore, lowering IOP cannot be considered the only target for glaucoma treatment and the search for new strategies, aimed at preventing or delaying retinal ganglion cell degeneration is a significant challenge for many researchers in the field.
Difficulties in identifying new targets arise from two partially unanswered questions: (1) what is the primum movens and (2) what is/are the molecular mechanism/s leading to RGCs death?
Several theories have been postulated and numerous factors have been charged. Stress factors identified as determinants in RGC death include: alteration of neurotrophin signaling, excitotoxicity, oxidative stress, mitochondrial dysfunction, protein misfolding and glial activation [4]. Other conditions act as co-factors including hypoxic and ischemic phenomena [5], genetic mutations [6] and auto-immunity [7].
Regardless of what determinant/s cause neurodegeneration in glaucoma, experimental and clinical evidence have shown that RGC death occurs through apoptosis [8]. This observation set the ground for a large amount of studies searching for anti-apoptotic strategies of neuroprotection. However, apoptosis is the very final, therefore often irreversible, step of the process and it is conceivable that the commitment to die is, at least partly, consequent to failure of endogenous protective pathways.
Autophagy can be envisaged as a protective pathway allowing the cells to cope with stressor conditions and representing, therefore, a promising target for potential glaucoma neuroprotection.
The aim of this review is to provide a brief synopsis on the autophagic process with a specific focus on its possible role in glaucoma neurodegeneration.
Section snippets
Autophagy machinery: mechanisms, function and dysfunction
Autophagy is an evolutionarily conserved process by which eukaryotic cells regulate the turnover of long-lived proteins and cytoplasmic organelles [9]. The process is executed at low basal levels in virtually all cells performing homeostatic functions, and it is induced as a catabolic adaptative process in response to different forms of stress, including starvation, growth factor withdrawal, hypoxia or accumulation of protein aggregates [10]. Activation of autophagy induced by several stressors
Autophagy and glaucoma: the hypothesis that lies beneath
Given the neurodegenerative nature of glaucoma, the hypothesis that autophagy is involved in RGC death stems from several considerations:
- (i)
neurons are highly vulnerable to autophagy dysfunction. It is established that neurons are metabolically highly active and their post mitotic nature translates into a limited or null potential of proliferating; accordingly, damaged or aged organelles and misfolded proteins cannot be redistributed among daughter cells and, if not efficiently removed, accumulate
Autophagy and retinal neuroprotection: where do we stand?
Despite the number of studies of autophagy in various neurodegenerative conditions, its role in retinal degeneration remains poorly understood. Most of the available studies concern the involvement of autophagy in photoreceptor degeneration, whilst very little is known regarding the role of autophagy in glaucoma-related RGC death; indeed this has only recently become an area of active research investigation.
Animal models of optic nerve crush/axotomy have been extensively used to study apoptosis
Conclusion
Our understanding of the role of autophagy in the pathogenesis of glaucoma is still at an early stage. Nevertheless, the experimental evidence gathered so far has demonstrated modulations of the autophagy pathway in RGCs in response to different stressors. From these observations one may hypothesis that alterations in the autophagic response might account for the susceptibility of RGCs to detrimental stimuli associated with the glaucomatous damage.
There is therefore the exciting prospect of
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens
2023, Progress in Retinal and Eye ResearchGlaucoma as a Neurodegenerative Disease: A Clinician Perspective
2021, Advances in Ophthalmology and OptometryEpigallocatechin-3-gallate stimulates autophagy and reduces apoptosis levels in retinal Müller cells under high-glucose conditions
2019, Experimental Cell ResearchCitation Excerpt :An increase of mTOR activity inhibits, while a decrease of mTOR activity promotes, the autophagic flux [20]. Autophagy has been recognized to be involved in the fate of stressed retinal neurons [21,22]. And the modulation of autophagic signalling, with consequent autophagy dysregulation, is likely to be involved in the pathogenesis of DR [23,24].
Autophagy-mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy
2018, Pharmacological ResearchCitation Excerpt :However, that neuronal injury plays a major role in DR is gaining increasing recognition [1–4]. Apoptotic pathways are known to participate in the death of retinal cells under different noxious stimuli, including diabetic stress, but autophagy, a catabolic pathway that promotes the degradation and recycling of cellular components, has also been recognized to be involved in the fate of stressed retinal neurons [5,6]. A variety of studies has been concerned with the possible roles of autophagy in DR [7–11].
Autophagy in the eye: Development, degeneration, and aging
2016, Progress in Retinal and Eye ResearchCitation Excerpt :It remains to be determined whether manipulation of autophagy can be exploited as a potential means of inducing RGC neuroprotection. To date rapamycin in the only pharmacological compound tested in animal models of glaucoma (Russo et al., 2013). Other better-tolerated rapalogs could also be candidate neuroprotectants.
New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system
2016, European Journal of PharmacologyCitation Excerpt :mTOR is the main negative regulator of the process which is orchestrated by 36 different autophagy-related genes (Atg) coordinating the formation of a double membrane structure (autophagosome) and its fusion with lysosomes where the cargo is degraded (Levine and Klionsky, 2004; Nakatogawa et al., 2009). Growing evidence supports the involvement of the autophagic process in the pathophysiology of glaucoma and several studies reported a dysregulation, either toward induction or inhibition, of the pathway (recently reviewed in Russo et al., 2013a, 2015b). Upregulation of Atg proteins were reported following optic nerve transection by Kim et al. (2008).