Our latest publication in the journal Nature is now avaliable!

Authors: Jennifer N. Rauch, Gabriel Luna, Elmer Guzman, Morgane Audouard, Collin Challis, Youssef E. Sibih, Carolina Leshuk, Israel Hernandez, Susanne Wegmann, Bradley T. Hyman, Viviana Gradniaru, Martin Kampmann, and Kenneth S. Kosik

Abstract:  The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies—including Alzheimer’s disease, frontotemporal dementia and chronic traumatic encephalopathy. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity. This observation and complementary experimental studies have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

Our latest publication in the journal Science Translational Medicine is now avaliable! The article in its entirety can be found here. I was fortunate enough to provide the imaging data for this project as part of the Kosik Molecular and Cellular Neurobiology lab. I was also lucky enough to have my image selected as a the journal cover.

Authors: Israel Hernandez, myself, Michel Giroux, Celeste Karch, Daniel Boctor, Youssef Sibih, Nadia Storm, Antonio Dias, Cezary Zekanowski, Alex Kang, Cassidy Hinman, Vesna Cerovac, Elmer Guzman, Honjun Zhou, Alison Goate, Steve Fisher, Ana Cuervo, Ken Kosik.

Abstract:
Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifi-cations of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in hu-man induced pluripotent stem cell–derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.

News and Media Coverage: Scientific American, The Conversation, Gizmodo, UC Santa Barbara, San Francisco Chronicle.

High-resolution, wide-field mosaic of the cerebellum.

Each year I look forward to the Nikon Small World International Photomicrography competition.  This year I was fortunate enough to receive image of distinction honors.  The Small World competition featured thousands of entries from 89 countries, showcasing some of the worlds best microscopists who share their talents in the premiere imaging contest.  I entered the image above of the cerebellum as part of my research in Dr. Kenneth Kosik’s cellular and molecular neurobiology lab in the Neuroscience Research Institute at UC Santa Barbara that was captured using immunoctyochemisty and a laser scanning confocal microscope.  The resultant image is comprised of hundreds of individual images or tiles that are seamlessly aligned and registered to provide both a global overview of the specimen as well as the resolution necessary to interrogate selected regions at the single-cell level.  The mosaic shows the Purkinje cells (red) lining the cerebellum, as well as the ubiquitous protein, tau (green) and nuclei (blue).  I have always been drawn to the cerebellum in part because of its sulci and gyri that demonstrate a remarkable sense of evolutionary complexity and aesthetic beauty.

Example of a single tile that comprise the above mosaic.

This example shows the resolution of a single tile that comprises the winning image.  Here, Perkinje cells stained with an antibody to inositol triphosphate 3 (green), the intermediate filament protein GFAP (glial fibrillary acidic protein; white), Bergmann’s glia (magenta), nuclei (blue) and myelin basic protein (red).

We have a new publication out in the journal of Investigative Ophthalmology and Visual Science that examined cellular and sub-cellular remodeling in the hibernating ground squirrel.  This research was a result of another fruitful collaboration with Ben Sajdak, a graduate student in the department of advanced ocular imaging program at the medical college of Wisconsin Eye Institute.  Open access PDF can be found here.

Authors: Benjamin S. Sajdak, Brent A. Bell, Taylor R. Lewis, myself, Grayson S. Cornwell, Steven K. Fisher, Dana K. Merriman, and Joesph Carroll.

Abstract:

Purpose. We examined outer retinal remodeling of the euthermic and torpid cone-dominant 13-lined ground squirrel (13-LGS) retina using optical coherence tomography (OCT) imaging and histology.

Methods. Retinas and corneas of living 13-LGSs were imaged during euthermic and torpid physiological states using OCT. Retinal layer thickness was measured at the visual streak from registered and averaged vertical B-scans. Following OCT, some retinas were collected immediately for postmortem histologic comparison using light microscopy, immunofluorescence, or transmission electron microscopy.

Results. Compared to OCT images from euthermic retinae, OCT images of torpid retinae revealed significantly thicker inner and outer nuclear layers, as well as increases in the distances between outer retinal reflectivity bands 1 and 2, and bands 3 and 4. A significant decrease in the distance between bands 2 and 3 also was seen, alongside significant thinning of the choriocapillaris and choroid. OCT image quality was reduced in torpid eyes, partly due to significant thickening of the corneal stroma during this state.

Conclusions. The torpid retina of the hibernating 13-LGS undergoes structural changes that can be detected by OCT imaging. Comparisons between in vivo OCT and ex vivo histomorphometry may offer insight to the origin of hyperreflective OCT bands within the outer retina of the cone-dominant 13-LGS.

Olympus flouview 1000 laser scanning confocal microscope.

Light micrograph using immunocytochemistry to visualize the cone photoreceptors of the neural retina, magnified 400 times.

Electron micrograph of the light sensitive photoreceptors, magnified 10,000 times.

Electron micrograph of a photoreceptor outer segment, magnified 20,000 times.

We have a new publication out in the journal glia that examines the role of the gene Sox2 on the development of astrocytes and the vasculature in the retina.  Read the full article here.

Authors: Amanda Kautzman, Patrick Keeley, Michael Nahmou, myself, Steven Fisher, Benjamin Reese

Abstract:  Sox2 is a transcriptional regulator that is highly expressed in retinal astrocytes, yet its function in these cells has not previously been examined. To understand its role, we conditionally deleted Sox2 from the population of astrocytes and examined the consequences on retinal development. We found that Sox2 deletion does not alter the migration of astrocytes, but it impairs their maturation, evidenced by the delayed upregulation of glial fibrillary acidic protein (GFAP) across the retina. The centro-peripheral gradient of angiogenesis is also delayed in Sox2-CKO retinas. In the mature retina, we observed lasting abnormalities in the astrocytic population evidenced by the sporadic loss of GFAP immunoreactivity in the peripheral retina as well as by the aberrant extension of processes into the inner retina. Blood vessels in the adult retina are also under-developed and show a decrease in the frequency of branch points and in total vessel length. The developmental relationship between maturing astrocytes and angiogenesis suggests a causal relationship between the astrocytic loss of Sox2 and the vascular architecture in maturity. We suggest that the delay in astrocytic maturation and vascular invasion may render the retina hypoxic, thereby causing the abnormalities we observe in adulthood. These studies uncover a novel role for Sox2 in the development of retinal astrocytes and indicate that its removal can lead to lasting changes to retinal homeostasis.