Curing blindness through molecular biology and genetics

A group of researchers at Scintillon Institute in San Diego, California and their collaborators identified important roles of myocyte enhancer factor 2 (MEF2) in the pathogenesis of stress-induced photoreceptor degeneration, a condition that is thought to contribute to eye diseases, such as retinitis pigmentosa and age-related macular degeneration, as described in their two recent publications (1,2). MEF2 is an activity-dependent transcription factor which is expressed in various organs, such as the heart, lymphocytes and brain. Dr. Stuart Lipton’s group has continuously worked on MEF2 since 1993, when they first isolated MEF2C, one of four mammalian MEF2 isoforms, in the developing brain. These researchers made seminal discoveries that established the notion that MEF2 transcription factors are prominent regulators of neurogenesis and neuronal survival in the brain. More recently, their work on MEF2C mutant mice led to the recognition of the human disease called MEF2C haploinsufficiency syndrome, in which children with heterozygous loss-of-function MEF2C mutations suffer from severe neurological conditions, including autism spectrum disorders, developmental and intellectual disabilities and seizures.

Scientists at the Neural Center of the Scintillon Institute have been expanding on MEF2 research, most recently turning their eyes to eye diseases (pun intended). Retinal photoreceptor cells express two MEF2 isoforms: MEF2C and MEF2D, the latter apparently being the predominant form. In a recent study, the researchers examined mutant mice completely lacking MEF2C or MEF2D (MEF2C- or MEF2D- “null” mice). Interestingly, both mutant mice developed drastic retinal degenerations by postnatal day 30. They then took a candidate approach to identify the molecular pathways affected by the loss of MEF2D in MEF2D-null mice. Among the pathways they examined was the PGC1α pathway, which regulates mitochondrial biogenesis and thereby protects cells from degeneration. The Lipton group determined that transcription of PGC1α was indeed reduced in MEF2D-null mice. Yet by overexpressing PGC1α in the retina of MEF2D-null mice, the researchers found that the retinal degeneration could be rescued.

In another related study, they examined mice lacking one copy of MEF2D (MEF2D-heteretozygous or “het” mice). Unlike MEF2D-null mice, MEF2D-het mice did not show any retinal regeneration when they were raised under normal housing environment. The researchers then exposed MEF2D-het mice to a strong white fluorescent light for 2 hours. While this light exposure did not induce any retinal degeneration in the wild-type mice, it did cause significant retinal cell death in MEF2D-het mice. The light exposure massively produced reactive oxygen species (ROS), which appeared to be the toxic cause. When searching for affected downstream pathways, they found that the transcription factor NRF2, a regulator of the cellular antioxidant defense response, fails to be induced by light exposure in MEF2D mutant mice. The researchers attempted to reverse light-induced retinal cell death by treating the MEF2D-het mice with carnosic acid, a chemical they had previously identified as a potent antioxidant and NRF2 activator. Intriguingly, treatment of carnosic acid drastically ameliorated the amount of light-induced retinal cell death in the mutant mice.

Together, these studies from the Scintillon Institute identify MEF2 transcription factors as crucial molecules in maintaining eye health. Importantly, they have shown that MEF2 and its downstream pathways can be targeted by drugs such as carnosic acid. Incidentally, carnosic acid is a naturally occurring chemical that is contained in herbs such as rosemary and sage. So, there may be a health benefit in cooking chicken and turkey with rosemary!

Within Scintillon Institute's Neural Center, the new Eye Research Center is being established, parallel to its Neural Degenerative Disease Center, through an ongoing fund-raising campaign, and is currently recruiting new faculty members.

 

1. Proc Natl Acad Sci USA 114, E4048

2. Inv Opthal Vis Sci 58, 3741

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Scintillon team to play key role in center for creating bioluminescent neuroscience tools

01 August 2017

FOR IMMEDIATE RELEASE

Scintillon team to play key role in center for creating bioluminescent neuroscience tools

San Diego, CA

In a new collaboration, scientists will advance and freely circulate a research technology that makes brain cells able to produce, respond to, and communicate with light.

Nathan Shaner, Ph.D. will lead Scintillon Institute’s contribution to a national center dedicated to developing and disseminating new tools based on bioluminescence. The five-year grant from the National Science Foundation aims to develop tools to give nervous system cells the ability to make and respond to light. Neuroscientists can use these tools to manipulate and observe the circuitry of the brain in a variety of model organisms.

 

“NeuroNex Technology Hub” is a new collaboration of labs at Brown University, Central Michigan University and the Scintillon Institute. The team will improve upon and combine several unique bioengineering technologies to create new research capabilities, rooted in bioluminescence-the natural ability of cells to make light. They will then make their advances rapidly, easily, and freely available to the global scientific community.  

 

Shaner joins co-principal investigators Diane Lipscombe, Brown professor of neuroscience and director of the Brown Institute for Brain Science, and Ute Hochgeschwender, professor at CMU, on a team led by Christopher Moore, a professor of neuroscience at Brown. Justine Allen, a Brown neuroscience PhD alumna, will be the center’s administrative director.

 

Creating a curriculum, which combines elements of biology, chemistry, physics and engineering, to engage and educate high school students will be a key facet of the center’s mission.

 

“The highly visual nature of this research is a great way to get young people interested in science,” said Shaner. “Being able to see living neurons lighting up as they fire under a microscope can be a transformative experience for them.”

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The US Department of Defense Funds New Direction in Monitoring and Stimulating Neurons for Directly Interfacing with the Brain

 

Jun 8, 2017, San Diego: Scintillon Institute Associate Professor Nathan Shaner is part of a nine-laboratory team that has been awarded a contract from the Defense Advanced Research Projects Agency (DARPA) as part of President Obama’s BRAIN Initiative. This project, dubbed “IBIS: Implantable bioluminescence interface system for an all-optical neuroprosthesis to the visual cortex,” will be funded under DARPA’s Neural Engineering System Design (NESD) program.

            Ultimately, the IBIS team seeks to develop a neural interface system capable of simultaneously recording from more than one million neurons and stimulating more than one hundred thousand neurons in regions of the human sensory cortex. Accomplishing this goal will be a huge leap forward from existing neural interfaces, which are limited to much smaller numbers of neurons, and are too bulky and invasive to be used in human therapies.

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Superresolution Microscopy in a new light

In 2014, the Nobel Prize in Chemistry was awarded to several scientists responsible for developing methods to break the resolution limits of optical microscopy. One technique pioneered by Dr. Eric Betzig, known as PALM microscopy, allows researchers to precisely measure the locations of single protein molecules within a cell, but unfortunately requires cells to be illuminated with such high light intensities that it can only be used reliably on fixed (dead) cells; living cells are often heavily damaged or even killed within minutes of observation using this technique.

In February 2017, Scintillon Institute Principal Investigator and Associate Professor Nathan Shaner, Ph.D. was awarded an R01 grant from the NIH's National Institute of General Medical Sciences (NIGMS) for the development of genetically encoded tools to solve this problem.

In order to allow researchers to observe single molecules in living cells without damaging them, Dr. Shaner will use bioluminescence - biologically-generated light that does not produce heat - to enable PALM-type imaging of individual proteins.

 

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Scintillon Institute receives BRAIN Initiative grant to expand optogenetics tools

Scintillon Institute Associate Professor Nathan Shaner, Ph.D. was awarded a U01 grant from the NIH's National Institute for Neurological Disorders and Stroke (NINDS) as part of the federal BRAIN initiative.  This grant will allow Dr. Shaner and his collaborators, Chris Moore, Ph.D.(Brown University) and Ute Hochgeschwender, M.D.(Central Michigan University), to expand the development of the non-invasive technology known as BioLuminescent OptoGenetics (BL-OG), which combines biological light production with light-sensitive proteins, allowing highly flexible manipulation of individual neurons.  

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