Snapshots of Life: Making the Brain Transparent

Brain webs

Credit: Ken Chan and Viviana Gradinaru Group, Caltech

What you are looking at above is something scientists couldn’t even dream of imaging less than a decade ago: bundles of neurons in the brainstem of an adult mouse. These bundles are randomly labeled with various colors that enable researchers to trace the course of each as it projects from the brainstem areas to other parts of the brain. Until recently, such a view would have been impossible because, like other organs, the brain is opaque and had to be sliced into thin, transparent sections of tissue to be examined under a light microscope. These sections forced a complex 3D structure to be visualized in 2D, losing critical detail about the connections.

But now, researchers have developed innovative approaches to make organs and other large volumes of tissue transparent when viewed with standard light microscopy [1]. This particular image was made using the Passive CLARITY Technique, or PACT, developed by the NIH-supported lab of Viviana Gradinaru at the California Institute of Technology (Caltech), Pasadena. Gradinaru has been working on turning tissues transparent since 2010, starting as a graduate student in the lab of CLARITY developer and bioengineering pioneer Karl Deisseroth at Stanford University. PACT is her latest refinement of the concept.

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LabTV: Curious About Parkinson’s Disease

Kinsley Belle

When the young scientist featured in this LabTV video first learned about induced pluripotent stem (iPS) cells a few years ago as an undergrad, he thought it would be cool if he could someday work with this innovative technology. Today, as a graduate student, Kinsley Belle is part of a research team that’s using iPS cells on a routine basis to gain a deeper understanding of Parkinson’s disease.

Derived from genetically reprogrammed skin cells or white blood cells, iPS cells have the potential to develop into many different types of cells, providing scientists with a powerful tool to model a wide variety of diseases in laboratory dishes.  At the University of Miami’s John P. Hussman Institute for Human Genomics, Belle and his colleagues are taking advantage of an iPS model of Parkinson’s disease to explore its molecular roots. Their goal? To use that information to develop better treatments or maybe even a cure for the neurodegenerative disorder that affects at least a half-million Americans.

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siRNAs: Small Molecules that Pack a Big Punch

Photo of parkin protein (green) that tags damaged mitochondria (red)

Caption: NIH scientists used RNA interference to find genes that interact with the parkin protein (green), which tags damaged mitochondria (red). Mutations in the parkin gene are linked to Parkinson’s disease and other mitochondrial disorders.
Credit: Richard J. Youle Laboratory, NINDS, NIH

It would be terrific if we could turn off human genes in the laboratory, one at a time, to figure out their exact functions and learn more about how our health is affected when those functions are disrupted. Today, I’m excited to announce the availability of new data that will empower researchers to do just that on a genome-wide scale. As part of a public-private collaboration between the NIH’s National Center for Advancing Translational Sciences (NCATS) and Life Technologies Corporation, researchers now have access to a wealth of information about small interfering RNAs (siRNAs), which are snippets of ribonucleic acid (RNA) with the power to turn off a gene, or reduce its activity—in much the same way that we use a dimmer switch to modulate a light.

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Yeast Reveals New Drug Target for Parkinson’s

Untreated yeast shows clumps of brightly colored spots, while treated yeast are more even in their color.

Caption: Left, yeast sick with too much α-synuclein, a protein that is implicated in Parkinson’s disease. Right, the same yeast cells after a dose of NAB, which seems to reverse the toxic effects of α-synuclein.
Credit: Daniel Tardiff, Whitehead Institute

Many progressive neurodegenerative disorders like Alzheimer’s, Huntington’s, and Parkinson’s disease, are characterized by abnormal clumps of proteins that clog up the cell and disrupt normal cellular functions. But it’s difficult to study these complex disease processes directly in the brain—so NIH-funded researchers, led by a team at the Whitehead Institute for Biomedical Research, Cambridge, MA, have turned to yeast for help.

Now, it may sound odd to study a brain disease in yeast, a microorganism long used in baking and brewing. After all, the brain is made up of billions of cells of many different types, while yeast grows as a single cell. But because the processes of protein production are generally conserved from yeast to humans, we can use this infinitely simpler organism to figure out what the proteins clumps are doing and test various drug candidates to halt the damage.

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New Insight into Parkinson’s Disease

Photos of a healthy brain cell and a brain cell affected by Parkinson's

Caption: (LEFT) A healthy neuron with the alpha-synuclein (green) protein diffusely spread in the cell. The bright reddish dots are the garbage disposal lysosomes with alpha-synuclein entering, which gives them an orange hue. (RIGHT) This is a sick neuron from a LRRK2 brain. The lysosomes are enlarged and puffy because the alpha-synuclein is stuck outside and unable to enter the trash.
Credit: Samantha Orenstein and Dr. Esperanza Arias, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York

I’m blogging today to tell you about a new NIH funded report [1] describing a possible cause of Parkinson’s disease: a clog in the protein disposal system.

You probably already know something about Parkinson’s disease. Many of us know individuals who have been stricken, and actor Michael J. Fox, who suffers from it, has done a great job talking about and spreading awareness of it. Parkinson’s is a progressive neurodegenerative condition in which the dopamine-producing cells in the brain region called the substantia nigra begin to sicken and die. These cells are critical for controlling movement; their death causes shaking, difficulty moving, and the characteristic slow gait. Patients can have trouble swallowing, chewing, and speaking. As the disease progresses, cognitive and behavioral problems take hold—depression, personality shifts, sleep disturbances.

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