Missense variant in CST3 Exerts Recessive Effect On Susceptibility to AMD

paraoan

There is an interesting paper out demonstrating that CST3 exerts a recessive effect on susceptibility to AMD.  Cystatin C is a potent inhibitor of cysteine proteinases expressed by many tissues and in the eye, it is highly expressed by the retinal pigment epithelium (RPE). The team led by Luminita Paraoan recently reported data identifying a polymorphism in the cystatin C gene (CST3) that increases the risk of two major degenerative diseases, age-related macular degeneration (AMD) and Alzheimer’s disease.  Both these multifactorial diseases involve the age-related accumulation of extracellular deposits, linked to dysregulation of protein homeostasis. Since the advent of the genome-wide association study (GWAS) many SNPs have been found to be associated with these two diseases. However the SNP in CST3, which translates into an amino acid change in the leader sequence of the precursor protein, is the first identified to increase the risk of developing both diseases. Moreover the authors demonstrate that the risk associated with the mutant allele follows the same recessive model for both diseases. Thus only those individuals with two copies of the mutant cystatin allele are at elevated risk of developing both diseases.

How To Make A Prosthetic Eye

One of my favorite movie lines is in Blade Runner when Hannibal Chew tells Roy Batty that he designed his eyes. Until reality catches up with science fiction, eye design is still in the hands of designing prosthetic and attractive, but non-functional eyes.

This intriguing video features David Carpenter of the Ocular prosthetics division of Moorfields Eye Hospital discussing how to make a prosthetic eye to replace one lost due to trauma or disease.  Every year, David and his team craft 1,400 customized prosthetic eyes for patients, filling a fundamental cosmetic need.

Retinal Astrocytic Hamartoma

Retinal-Astrocytic-Hamartoma

This is a 58 year old white female with a retinal astrocytic hamartoma on her right optic nerve.  Retinal astrocytic hamartomas are glial tumors of the retinal nerve fiber layer arising from retinal astrocytes.

This animated GIF file illustrates the height of the hamartoma and is another example of where animated gifs can be a fantastic teaching tool.

The left and right stereo images shown were taken with a Zeiss FF-4 Fundus camera by James Gilman of the Moran Eye Center.

 

Müller Cell Metabolic Chaos During Degeneration

Muller-cell-chaos1 copy

This abstract was presented today at the 2015 Association for Research in Vision and Opthalmology (ARVO) meetings in Denver, Colorado by  Rebecca L. PfeifferBryan W. Jones and Robert E. Marc.

Purpose: Müller cells (MCs) play a critical role in glutamate (E) metabolism and carbon skeleton cycling in retina. MCs demonstrate changes in metabolism and morphology during retinal degeneration. The timing, extent, regulation, and impacts of these changes are not yet known. We evaluated metabolic phenotypes of MCs and evaluated their capacity to transport glutamate during degeneration.

Methods: Retinas were harvested from wild-type (WT) and rhodopsin Tg P347L rabbits, divided into chips mounted on filters, and incubated in Ames medium with 5 mM D-aspartate (D-Asp), D-glutamate (D-Glu), or D-glutamine (D-Gln) for 10 min at 35 deg to explore transport and metabolism. Chips were fixed in mixed aldehydes and resin embedded for computational molecular phenotyping (CMP) of a range of L- and D-amino acid markers and selected proteins including glutamine synthetase (GS) (J Comp Neurol. 464:1, 2003).

Results: CMP revealed wide variations in metabolite levels across individual MCs from Tg P347L retinas, generating chaotic patterns. GS decreased significantly while glutamine levels (Q) increased, although to varying degrees. Remarkably, E levels were variable and much higher in some MCs than normal, but did not correlate (inversely) with GS levels. Transport experiments using D-Glu, D-Asp, and D-Gln showed that alterations in MC metabolites are not the product of defective transporters, in contrast to previous reports. These results are also inconsistent with conventional models of GS-based E-Q metabolism and microenvironmental regulation of MC phenotypes.

Conclusions: These observations suggest three conclusions. (1) Although degeneration of the retina is certainly the trigger, MC phenotype changes are not a coherent response to the surrounding microenvironment but are, rather, uncoordinated individual MC responses. (2) Although GS is accepted as the primary enzyme responsible for the conversion of E to Q in the normal retina, alternative pathways appear unmasked in the degenerate state. (3) It has been previously hypothesized that MCs in retinal degenerations exhibit deficient E transport. Our experiments show no transport deficiency. This indicates that chaotic metabolite levels emerge from changes in individual MC metabolic processing.

Flying to ARVO 2015

Clouds

We are on our way to ARVO, 2015 in Denver, Colorado to participate in the largest gathering of vision scientists and clinicians in the world.  It’s the annual meeting of researchers presenting and discussing all things vision and ophthalmology.

If you are going to be at ARVO and want to meet up, leave us a comment here or send a Tweet to @Webvision1.

Look forward to seeing you there.

Harris Ripps Memorial At ARVO

Harris Ripps

At this year’s ARVO meeting in Denver, please join us for a session honoring the memory of Dr. Harris Ripps.

Tuesday 1:00 pm – 2:30 pm

Room 708/710/712

Dr. Harris Ripps (1927 – 2014), Proctor Medal winner and past ARVO President, devoted his scientific career to studies on the retina and on causes of visual loss in inherited retinal diseases. He made significant contributions in many areas of vision research, including the kinetics of visual pigment bleaching and regeneration, electrical and chemical communication among retinal neurons and glia, and the cellular mechanisms of retinal degeneration. This memorial session will celebrate Dr. Ripps’ long time vision research career with talks by several his colleagues and students. The audience is welcome to contribute remarks during the open period of the session.

Session chair: John Dowling, Ph.D., Department of Molecular and Cellular Biology, Harvard University

Speakers:

Bradford Ripps, O.D., Total Eyecare, New Jersey
Richard Chappell, Ph.D., Marine Biological Laboratory, Massachusetts
David Pepperberg, Ph.D., Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago
Robert Paul Malchow, Ph.D., Department of Biological Sciences, University of Illinois at Chicago
Haohua Qian, Ph.D., National Eye Institute
Muna Naash, Ph.D., Department of Cell Biology, University of Oklahoma Health Sciences Center
John O’Brien, Ph.D., Department of Ophthalmology and Visual Science, University of Texas
Wen Shen, Ph.D., Department of Biomedical Science, Florida Atlantic University

 

Evo Devo Connectomics Of Sensory Circuit For Visual Navigation

EvoDevo vision

There is an interesting paper from an evo devo perspective out of the Jékely laboratory, looking at the connectomics of some of the earliest of organized visual systems in the Platynereis dumerilii larva.  They have described a visual circuit consisting of 71 neurons and 1,106 “connections”.  The cool thing about this study was that they were also able to combine behavioral experiments with ablations revealing the ability to detect spatial light, directing movement or taxis in the direction of the light.

Its too bad I did not visit with them last time I was in Tübingen as it would have been good to talk connectomics and techniques with them.  I am encouraged that they used serial section transmission electron microscopy to perform circuit level analysis as we think its the right approach for circuit level analysis, though I worry that the resolution was too low to image gap junctions, though they did mention looking for them.  Regardless, I would have loved to see their setup and talked with them.

 

 

Lasker/IRRF Report On Restoring Vision

Restoring Vision To The Blind

I participated in the Lasker/IRRF Initiative on Restoring Vision to the Blind in March 2014. It was a great session of research leaders working on various approaches to restore visual function lost by retinal degenerative disease. The purpose of the meeting was to identify the key issues hampering research progress and to develop innovative proposals to overcome these hurdles and accelerate research. The Initiative prepared a report of its findings that ARVO published as a special edition of its online journal Translation Vision Science and Technology. It can be viewed at http://tvstjournal.org/toc/tvst/3/7.

I am attaching the Table of Contents for the report, along with John Dowling’s introduction to give you an idea of the scope of the work discussed by participants.  If you want a pdf of the entire report, you can find it on the Lasker website at: http://www.laskerfoundation.org/programs/images/irrf_15.pdf . A print copy of the report is also available by writing to Meredith Graves as mgraves@laskerfoundation.org

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Notable Paper: Reproducibility in Science

Reproducability in Science

This article by C. Glenn Begley and John P.A. Ioannidis is not specifically vision related, but is more generally applicable to research integrity and is well worth a read, in particular the following paragraph:

“What has shaken many in the field is not that investigators are unable to precisely reproduce an experiment. That is to be expected. What is shocking is that in many cases, the big idea or major conclusion was not confirmed simply when experi- ments were performed by the same investigators when blinded to their test samples versus control samples.2 The explanation for this was evident when the precise methodology of the experiments was reviewed. Investigators typically performed their experiments in a nonblinded fashion, so they were able to see what they were anticipating to see, and their research bias was thus able to be confirmed.18 Observer bias has long been recognized to be a problem in preclinical studies and beyond, so this result should not be surprising.19 Confirmation bias in scientific investigation unavoidably makes even the best scientists prone to try to find results or interpretations that fit their preconceived ideas and theories.20,21”

 

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