Exosomes and alpha-synuclein within retina from autophagy to protein spreading in neurodegeneration

Pinelli, Roberto; Bertelli, Matteo; Scaffidi, Elena; Busceti, Carla Letizia; Biagioni, Francesca; Fornai, Francesco

doi:10.12871/00039829202114

Cited by 3 publications

(16 citation statements)

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“…The occurrence of retinal degeneration is postulated to derive from focal subcellular autophagy impairment at various retinal levels (Pinelli et al, 2020c), and it may serves to distinguish between different phenotypes of retinal degeneration (Pinelli et al, 2020c;Kim et al, 2021;Shijo et al, 2021;Wu et al, 2021). In fact, according to the hypothesis of an exosome-dependent trafficking of misfolded proteins towards different poles of the retina, as inferred by pre-clinical studies (Pinelli et al, 2020c;2021a;2021b), various autophagy-mediated pathogenic mechanisms within the retina may be implicated. In detail, the updated retinal microanatomy indicates that RPE as well as Muller cells act as a pivot to grant outer and inner retinal metabolism (Gass, 1972;Ambati and Fowler, 2012;Boulton and Dayhaw-Barker, 2001;Bonilha, 2008;Kozlowski, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In this way, the sub-cellular organelles and biochemical responses to varying insults depend on these cells to produce the onset and progression of retinal damage. As summarized in Pinelli et al (2020c) these include (i) a failure in retinal protection from oxidative and mitochondrial stress; (ii) a loss of ability to cope with lipid, glycogen, and protein overload; (iii) impaired renewal; (iv) a loss of the outer blood-retinal barrier; (v) the occurrence of abnormal inflammatory/immune response; (vi) a loss of retinal polarity, thus reverting the metabolic flow towards photoreceptor and from the choroid; (vii) accumulation via an exosome dependent process of extracellular waste material including proteins advanced glycation end products (AGEs) and lipids (Pinelli et al, 2021a). All these effects appear to be under the influence of the autophagy status within the retina.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, stem cell in the CNS are strongly stimulated to proliferate and differentiate towards a neuronal phenotype following autophagy activation (Chang et al, 2020). In recent reports we provided evidence showing that autophagy activation may sort protective effects and promote anatomical and functional recovery in the retina affected by chronic degeneration (Pinelli et al, 2020b(Pinelli et al, , 2020c2020d;2021a;2021b). In fact, the autophagy status of a number of retinal cells is key in promoting the integrity of the retina.…”

Section: Introductionmentioning

confidence: 99%

“…In this way, even focal alterations in the autophagy machinery affecting subcellular domain may play a role in conditioning retinal integrity (Pinelli et al, 2020c). Again, the ability of autophagy to alter the trafficking of exosomes across various retinal layers may explain the progression of autophagy-dependent beneficial or deleterious effects across the whole retina as inferred by pre-clinical studies (Pinelli et al, 2020c;2021a;2021b). Various autophagy-mediated pathogenic mechanisms for retinal degeneration are implicated.…”

Section: Introductionmentioning

confidence: 99%

“…Various autophagy-mediated pathogenic mechanisms for retinal degeneration are implicated. As previously hypothesized, Pinelli et al (2020c), autophagy alterations may lead to several effects in the retina such as: (i) a deficiency of retinal protection against oxidative stress, free radicals and mitochondrial alterations; (ii) a loss of ability to counteract an overload of lipids, glycated products, and amino acids; (iii) a loss of stimulation of retinal regeneration through an impairment of specific niche of stem cells; (iv) an alteration of the blood-retinal barrier, which may no longer preserve retinal cells from circulating toxic species; (v) a loss of regulation of the retinal immune response, which may trigger an abnormal inflammation; (vi) a loss of polarity within the retina concerning metabolism and cell-to-cell communication; (vii) abnormal production of exosomes which may not protect the retinal tissue or may promote the occurrence of altered retinal plasticity (Pinelli et al, 2021a). Muller cells and specific retinal neurons undergo similar autophagy-dependent alterations.…”

Section: Introductionmentioning

confidence: 99%

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Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Pinelli¹,

Berti²,

Scaffidi³

et al. 2022

Archives Italiennes De Biologie

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The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Pinelli¹,

Berti²,

Scaffidi³

et al. 2022

Archives Italiennes De Biologie

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Autophagy Activation Promoted by Pulses of Light and Phytochemicals Counteracting Oxidative Stress during Age-Related Macular Degeneration

Pinelli¹,

Ferrucci

Biagioni

et al. 2023

Antioxidants

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The seminal role of autophagy during age-related macular degeneration (AMD) lies in the clearance of a number of reactive oxidative species that generate dysfunctional mitochondria. In fact, reactive oxygen species (ROS) in the retina generate misfolded proteins, alter lipids and sugars composition, disrupt DNA integrity, damage cell organelles and produce retinal inclusions while causing AMD. This explains why autophagy in the retinal pigment epithelium (RPE), mostly at the macular level, is essential in AMD and even in baseline conditions to provide a powerful and fast replacement of oxidized molecules and ROS-damaged mitochondria. When autophagy is impaired within RPE, the deleterious effects of ROS, which are produced in excess also during baseline conditions, are no longer counteracted, and retinal degeneration may occur. Within RPE, autophagy can be induced by various stimuli, such as light and naturally occurring phytochemicals. Light and phytochemicals, in turn, may synergize to enhance autophagy. This may explain the beneficial effects of light pulses combined with phytochemicals both in improving retinal structure and visual acuity. The ability of light to activate some phytochemicals may further extend such a synergism during retinal degeneration. In this way, photosensitive natural compounds may produce light-dependent beneficial antioxidant effects in AMD.

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The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration

Pinelli

Ferrucci

Berti

et al. 2023

IJMS

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The present article discusses the role of light in altering autophagy, both within the outer retina (retinal pigment epithelium, RPE, and the outer segment of photoreceptors) and the inner choroid (Bruch’s membrane, BM, endothelial cells and the pericytes of choriocapillaris, CC). Here autophagy is needed to maintain the high metabolic requirements and to provide the specific physiological activity sub-serving the process of vision. Activation or inhibition of autophagy within RPE strongly depends on light exposure and it is concomitant with activation or inhibition of the outer segment of the photoreceptors. This also recruits CC, which provides blood flow and metabolic substrates. Thus, the inner choroid and outer retina are mutually dependent and their activity is orchestrated by light exposure in order to cope with metabolic demand. This is tuned by the autophagy status, which works as a sort of pivot in the cross-talk within the inner choroid/outer retina neurovascular unit. In degenerative conditions, and mostly during age-related macular degeneration (AMD), autophagy dysfunction occurs in this area to induce cell loss and extracellular aggregates. Therefore, a detailed analysis of the autophagy status encompassing CC, RPE and interposed BM is key to understanding the fine anatomy and altered biochemistry which underlie the onset and progression of AMD.

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Exosomes and alpha-synuclein within retina from autophagy to protein spreading in neurodegeneration

Cited by 3 publications

References 0 publications

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Autophagy Activation Promoted by Pulses of Light and Phytochemicals Counteracting Oxidative Stress during Age-Related Macular Degeneration

The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration

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