Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival

Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the retina represents an interesting scenario to appreciate the various functions of this organelle in both physiological and pathological conditions. Growing evidence suggests a role for lysosome-related mechanisms in retinal degeneration. Abnormal lysosomal activation or inhibition has dramatic consequences on photoreceptor cell homeostasis and impacts extensive cellular function, which in turn affects vision. Based on these findings, a series of therapeutic methods targeting lysosomal processes could offer treatment for blindness conditions. Here, we review the recent findings on membrane trafficking, subcellular organization, mechanisms by which lysosome/autophagy pathway impairment affects photoreceptor cell homeostasis and the recent advances on developing efficient lysosomal-based therapies for retinal disorders.

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Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Cell Death and Disease ◽

10.1038/s41419-021-04482-1 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Soumyaparna Das ◽

Valerie Popp ◽

Michael Power ◽

Kathrin Groeneveld ◽

Jie Yan ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Strong Increase ◽

Channel Blockers ◽

Photoreceptor Degeneration ◽

Therapy Development ◽

Hypertensive Drug ◽

Future Therapy

AbstractHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

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Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

PLoS ONE ◽

10.1371/journal.pone.0239108 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0239108

Author(s):

Ryo Terauchi ◽

Hideo Kohno ◽

Sumiko Watanabe ◽

Saburo Saito ◽

Akira Watanabe ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Fluorescent Protein ◽

Outer Nuclear Layer ◽

Inhibitory Effect ◽

Subretinal Space ◽

Photoreceptor Degeneration ◽

Retinal Inflammation ◽

Green Fluorescent

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

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Control of the Nucleotide Cycle in Photoreceptor Cell Extracts by Retinal Degeneration Protein 3

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2018.00052 ◽

2018 ◽

Vol 11 ◽

Cited By ~ 4

Author(s):

Hanna Wimberg ◽

Ulrike Janssen-Bienhold ◽

Karl-Wilhelm Koch

Keyword(s):

Retinal Degeneration ◽

Photoreceptor Cell ◽

Cell Extracts

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Modulation of Autophagy for Controlling Immunity

Cells ◽

10.3390/cells8020138 ◽

2019 ◽

Vol 8 (2) ◽

pp. 138 ◽

Cited By ~ 18

Author(s):

Young Jin Jang ◽

Jae Hwan Kim ◽

Sanguine Byun

Keyword(s):

Immune Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Mechanisms Of Action ◽

Innate And Adaptive Immunity ◽

Pathological Conditions ◽

Physiological Homeostasis ◽

Autophagy Pathway ◽

Key Steps ◽

Additional Role

Autophagy is an essential process that maintains physiological homeostasis by promoting the transfer of cytoplasmic constituents to autophagolysosomes for degradation. In immune cells, the autophagy pathway plays an additional role in facilitating proper immunological functions. Specifically, the autophagy pathway can participate in controlling key steps in innate and adaptive immunity. Accordingly, alterations in autophagy have been linked to inflammatory diseases and defective immune responses against pathogens. In this review, we discuss the various roles of autophagy signaling in coordinating immune responses and how these activities are connected to pathological conditions. We highlight the therapeutic potential of autophagy modulators that can impact immune responses and the mechanisms of action responsible.

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Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration

Molecular Neurobiology ◽

10.1007/s12035-008-8045-9 ◽

2008 ◽

Vol 38 (3) ◽

pp. 253-269 ◽

Cited By ~ 168

Author(s):

Javier Sancho-Pelluz ◽

Blanca Arango-Gonzalez ◽

Stefan Kustermann ◽

Francisco Javier Romero ◽

Theo van Veen ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Cell Death Mechanisms ◽

Inherited Retinal Degeneration

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Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00095.2016 ◽

2016 ◽

Vol 310 (11) ◽

pp. G1102-G1117 ◽

Cited By ~ 29

Author(s):

Yaron Ilan

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Potential Role ◽

Cell Organelles ◽

Secondary Messenger ◽

Pathological Conditions ◽

Messenger Molecules

The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.

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Extracellular Vesicles as Biological Shuttles for Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms20081848 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1848 ◽

Cited By ~ 20

Author(s):

Stefania Raimondo ◽

Gianluca Giavaresi ◽

Aurelio Lorico ◽

Riccardo Alessandro

Keyword(s):

Extracellular Vesicles ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

Target Cells ◽

Special Focus ◽

Pathological Conditions ◽

Critical Issues ◽

Membrane Bound ◽

And Function ◽

Potential Use

The development of effective nanosystems for drug delivery represents a key challenge for the improvement of most current anticancer therapies. Recent progress in the understanding of structure and function of extracellular vesicles (EVs)—specialized membrane-bound nanocarriers for intercellular communication—suggests that they might also serve as optimal delivery systems of therapeutics. In addition to carrying proteins, lipids, DNA and different forms of RNAs, EVs can be engineered to deliver specific bioactive molecules to target cells. Exploitation of their molecular composition and physical properties, together with improvement in bio-techniques to modify their content are critical issues to target them to specific cells/tissues/organs. Here, we will discuss the current developments in the field of animal and plant-derived EVs toward their potential use for delivery of therapeutic agents in different pathological conditions, with a special focus on cancer.

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