Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V

The evolutionarily conserved Crumbs (Crb) complex is crucial for photoreceptor morphogenesis and homeostasis. Loss of Crb results in light-dependent retinal degeneration, which is prevented by feeding mutant flies carotenoid-deficient medium. This suggests a defect in rhodopsin 1 (Rh1) processing, transport, and/or signaling, causing degeneration; however, the molecular mechanism of this remained elusive. In this paper, we show that myosin V (MyoV) coimmunoprecipitated with the Crb complex and that loss of crb led to severe reduction in MyoV levels, which could be rescued by proteasomal inhibition. Loss of MyoV in crb mutant photoreceptors was accompanied by defective transport of the MyoV cargo Rh1 to the light-sensing organelle, the rhabdomere. This resulted in an age-dependent accumulation of Rh1 in the photoreceptor cell (PRC) body, a well-documented trigger of degeneration. We conclude that Crb protects against degeneration by interacting with and stabilizing MyoV, thereby ensuring correct Rh1 trafficking. Our data provide, for the first time, a molecular mechanism for the light-dependent degeneration of PRCs observed in crb mutant retinas.

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Biosynthetic strategies for tetramic acid formation

Natural Product Reports ◽

10.1039/d0np00099j ◽

2021 ◽

Author(s):

Xuhua Mo ◽

Tobias A. M. Gulder

Keyword(s):

Molecular Mechanism ◽

Gene Clusters ◽

Acid Formation ◽

Biosynthetic Gene ◽

Tetramic Acid ◽

Biosynthetic Gene Clusters ◽

The Individual ◽

First Time ◽

Acid Unit

Over 30 biosynthetic gene clusters for natural tetramate have been identified. This highlight reviews the biosynthetic strategies for formation of tetramic acid unit for the first time, discussing the individual molecular mechanism in detail.

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CHARACTERISTICS OF AGE-DEPENDENT CHANGES IN THE URINE'S PROTEOM COMPOSITION OF THE HEALTHY PERSONS (EXPERIMENTAL AND THEORETICAL STUDY)

Успехи геронтологии ◽

10.34922/ae.2020.33.4.016 ◽

2020 ◽

pp. 735-740

Author(s):

Л. Х. Пастушкова ◽

Д. Н. Каширина ◽

А. Г. Гончарова ◽

Н. Б. Захарова ◽

Е. С. Тийс ◽

...

Keyword(s):

Signaling Pathway ◽

Insulin Signaling ◽

Defense Mechanisms ◽

Theoretical Study ◽

Clinical Manifestations ◽

Age Dependent ◽

First Time ◽

Healthy Persons ◽

Over Time

Впервые описаны белки, достоверно увеличивающиеся и уменьшающиеся в моче с возрастом в интервале 20-60 лет. Охарактеризованы комбинации белков, связанных с изменением иммунных процессов, нарушением реологии крови, в том числе риском коагулопатии, противоопухолевых защитных механизмов, инсулинового сигнального пути, с изменением характеристик клеточного деления и качества новообразованной ткани. Таким образом, возрастная динамика основных процессов запускает каскад реакций, проявляющихся в замыкании «патологических биохимических кругов», которые формируют предпосылки к развитию заболеваний и, с течением времени, клинические проявления. For the ﬁrst time proteins are described, reliably increasing and decreasing in urine with age in the range of 20 to 60 years. The combinations of proteins associated with changes in immune processes, violation of blood reology, including the risk of coagulopathy, anticancer defense mechanisms, insulin signaling pathway, changes in cell characteristics are characterized division and quality of the newly formed fabric. Thus, the age dynamics of the main processes triggers a cascade of reactions manifested in the closure of «pathological biochemical circles» that form the prerequisites for the development of diseases and, over time, clinical manifestations.

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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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The Molecular Mechanism of Retinal Degeneration in the Retinal Degeneration B (rdgB) Mutant of Drosophila

Signal Transduction in Photoreceptor Cells - Research Reports in Physics ◽

10.1007/978-3-642-76482-0_20 ◽

1992 ◽

pp. 281-298

Author(s):

B. Minke ◽

C. T. Rubinstein ◽

I. Sahly ◽

S. Bar-Nachum ◽

E. Suss ◽

...

Keyword(s):

Retinal Degeneration ◽

Molecular Mechanism

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Microtubule aging probed by microfluidics-assisted tubulin washout

Molecular Biology of the Cell ◽

10.1091/mbc.e16-07-0548 ◽

2016 ◽

Vol 27 (22) ◽

pp. 3563-3573 ◽

Cited By ~ 18

Author(s):

Christian Duellberg ◽

Nicholas Ian Cade ◽

Thomas Surrey

Keyword(s):

Molecular Mechanism ◽

Growth Phase ◽

Morphological Changes ◽

Threshold Model ◽

Theoretical Models ◽

Age Dependence ◽

Microtubule Depolymerization ◽

Microtubule Stability ◽

Age Dependent

Microtubules switch stochastically between phases of growth and shrinkage. The molecular mechanism responsible for the end of a growth phase, an event called catastrophe, is still not understood. The probability for a catastrophe to occur increases with microtubule age, putting constraints on the possible molecular mechanism of catastrophe induction. Here we used microfluidics-assisted fast tubulin washout experiments to induce microtubule depolymerization in a controlled manner at different times after the start of growth. We found that aging can also be observed in this assay, providing valuable new constraints against which theoretical models of catastrophe induction can be tested. We found that the data can be quantitatively well explained by a simple kinetic threshold model that assumes an age-dependent broadening of the protective cap at the microtubule end as a result of an evolving tapered end structure; this leads to a decrease of the cap density and its stability. This analysis suggests an intuitive picture of the role of morphological changes of the protective cap for the age dependence of microtubule stability.

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Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains

Journal of Central Nervous System Disease ◽

10.4137/jcnsd.s14012 ◽

2014 ◽

Vol 6 ◽

pp. JCNSD.S14012 ◽

Cited By ~ 10

Author(s):

Seok K. Kang ◽

Shin Tae Kim ◽

Michael V. Johnston ◽

Shilpa D. Kadam

Keyword(s):

Acid Decarboxylase ◽

Gaba Transporter ◽

Motor Disabilities ◽

Gaba Transporters ◽

Age Dependent ◽

Progressive Neurodegeneration ◽

Gabaergic Synapses ◽

Cell Densities ◽

Gaba Transporter 1 ◽

First Time

Rett syndrome (RTT), associated with mutations in methyl-CpG-binding protein 2 (Mecp2), is linked to diverse neurological symptoms such as seizures, motor disabilities, and cognitive impairments. An altered GABAergic system has been proposed as one of many underlying pathologies of progressive neurodegeneration in several RTT studies. This study for the first time investigated the temporal- and location-specific alterations in the expression of γ-amino butyric acid (GABA) transporter 1 (GAT-1), vesicular GABA transporter (vGAT), and glutamic acid decarboxylase 67kD (GAD67) in wild type (WT) and knockout (KO) mice in the Mecp2m1.1Bird/y mouse model of RTT. Immunohistochemistry (IHC) co-labeling of GAT-1 with vGAT identified GABAergic synapses that were quantitated for mid-sagittal sections in the frontal cortex (FC), hippocampal dentate gyrus (DG), and striatum (Str). An age-dependent increase in the expression of synaptic GABA transporters, GAT-1, and vGAT, was observed in the FC and DG in WT brains. Mecp2 KO mice showed a significant alteration in this temporal profile that was location-specific, only in the FC. GAD67-positive cell densities also showed an age-dependent increase in the FC, but a decrease in the DG in WT mice. However, these densities were not significantly altered in the KO mice in the regions examined in this study. Therefore, the significant location-specific downregulation of synaptic GABA transporters in Mecp2 KO brains with unaltered densities of GAD67-positive interneurons may highlight the location-specific synaptic pathophysiology in this model of RTT.

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Year-class detection reveals climatic modulation of settlement strength in the European lobster, Homarus gammarus

Canadian Journal of Fisheries and Aquatic Sciences ◽

10.1139/f02-083 ◽

2002 ◽

Vol 59 (7) ◽

pp. 1132-1143 ◽

Cited By ~ 19

Author(s):

M R.J Sheehy ◽

R C.A Bannister

Keyword(s):

Stock Assessment ◽

Global Climate ◽

Larval Settlement ◽

European Lobster ◽

Homarus Gammarus ◽

Cross Correlation Analysis ◽

Age Dependent ◽

Intractable Problem ◽

First Time

Understanding the nature of recruitment relationships in the European lobster, Homarus gammarus, has been an intractable problem because of difficulties associated with quantification of its scarce planktonic larvae and early benthic phase. We attempt to address this problem by analyzing the age composition of a population off the northeast coast of England. Age-dependent in situ deposits of neurolipofuscin in the eyestalk are used as an age index. An approach is presented that accounts and (or) corrects for the two most important potential sources of error in age determinations by this technique, namely environmental temperature variation and unexplained individual variation. This yields, for the first time in very long-lived clawed lobsters, reproducible catch age structures with year-class resolution. The method should be generally applicable to crustaceans. Cross-correlation analysis shows that larval settlement strength in the European lobster is associated with local sea temperatures and onshore winds in a manner similar to that reported for other lobsters. These findings have important implications for stock assessment, particularly the use of traditional models dependent on size and steady state, yield forecasting, the effects of global climate change, arguments about spawner protection or restocking, and the spawnerrecruit relationship.

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