Scientific Advancements

2a-researc-scientific-advance

The drive to advance our scientific understanding of the brain and improve lives is the motivating force propelling our investigators, our students and our funding partners to new research heights. We’re proud of the notable accomplishments our ZNI researchers have made to date.

Alzheimer and Related Diseases

Chang Lab
Alzheimer and Related Diseases
Karen Chang, PhD, assistant professor of cell and neurobiology, Zilkha Neurogenetic Institute

The Chang lab discovered the following things: 1) a protein upregulated in both Down syndrome and Alzheimer’s disease plays a surprisingly role in delaying neurodegeneration; 2) a kinase mutated in autism and upregulated in Down syndrome enhances the rate of recycling of neurotransmitters required for reliable communication between neurons. They are continuing to investigate the biological functions of both of these proteins and their contribution to neurological disorders.

Dong Lab
Alzheimer and Related Diseases
Hong-Wei Dong, MD, PhD, associate professor of Neurology, Institute of Neuroimaging and Informatics

The Dong lab made a significant progress on the NIH-funded Mouse Connectome Project (MCP, www.MouseConnectome.org), which proposes to generate the connectivity map of the entire mammalian brain and to subsequently construct its neural networks using computational technology. The MCP has produced one of the first online digital connectivity atlases, the iConnectome, which hosts ~8,200 regular users. The team has traced 600 cortical pathways and has generated the most comprehensive connectivity matrix of the mammalian cerebral cortex. Their interactive cortical connectomic map, which features hundreds of reconstructed cortical pathways, is also available online. The data were also subjected to graph theoretical analyses, which revealed that the cortex is organized into a few relatively segregated networks. This novel work was recently published (Zingg et al., Cell 156, 1096-1111, 2014). Because of its broad scientific relevance, Cell Press and USC did a press release on the article. And it was featured on the NIH director’s blog, and was nationally recognized in the recent Interim report of the BRAIN initiative. These accomplishments were contingent upon innovative developments including pipelines for collecting, presenting, and analyzing large-scale connectivity.

Langen Lab
Alzheimer and Related Diseases
Ralf Langen, PhD, professor of biochemistry and molecular biology, Zilkha Neurogenetic Institute

During the past year, the Langen group continued to investigate what makes proteins misfold and take up toxic species in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and type-2 diabetes. Toward this end, they obtained novel structural information of several toxic misfolded amyloidogenic states and further developed peptide and protein-based means for inhibiting the misfolding and, thereby, preventing toxicity. The studies by the Langen group also provide insight into how environmental factors that can promote the aforementioned diseases do so by affecting protein misfolding. In collaboration with the biotechnology company PROMIDIS, the Langen group also identified a new structural state of the Huntington’s disease causing protein htt, and prevention of this structural form by post-translational modifications or small molecules is thought to be a therapeutic target. In separate studies, the Langen group identified a new mechanism, by which cells can control the shape of cellular membranes. In particular, it was found that the same protein can generate different types of curvature and that phosphorylation acts as a molecular switch that determines which membrane curvature is generated. The involvement of this switch is likely to be of relevance in several diseases, including Parkinson’s disease.

Siemer Lab
Alzheimer and Related Diseases
Ansgar Siemer, PhD, assistant professor of biochemistry and molecular biology, Department of Biochemistry and Molecular Biology

The major goal of Siemer lab is to describe on a structural level how some amyloid fibrils can be toxic and responsible for neurodegenerative diseases, while others have beneficial functions as for example in long-term memory. The latter question is addressed in their research on the Orb2 functional amyloid, which is a key regulator of long-term memory in Drosophila. Besides considerable progress in defining the extent and the structure of Orb2’s amyloid core, they found that Orb2 has previously undescribed affinities to metal ions, lipids, and nucleic acids. They are following up on these finding to understand the importance of these interactions for long-term memory. Their research on the origin of toxic amyloids in neurodegenerative diseases is done in collaboration with the lab of Ralf Langen where they are working on the structure of toxic fibrils formed by the protein huntingtin, important in Huntington’s Disease. With the lab’s newly installed solid-state NMR spectrometer, they could detect clear structural and dynamical differences between highly toxic amyloid fibrils and fibrils that were shown to be less toxic. In a next step, the Langen and Siemer labs will solve the structure of both the toxic and the benign huntingtin fibrils, which will give them important clues about how some amyloid fibrils can be toxic and others not.

Town Lab
Alzheimer and Related Diseases
Terrence Town, PhD, visiting professor of physiology and biophysics, Zilkha Neurogenetic Institute

The Town lab’s focus is to develop a treatment for Alzheimer’s disease by targeting the body’s immune system. Most therapies targeting the disease are thwarted by the blood-brain barrier, a natural mechanism that protects brain cells from entry of peripheral substances, and by the fact that immune responses in the brain are typically muted. However, in laboratory mice programmed to develop Alzheimer’s-like disease, the Town group has shown that certain immune cells can be coaxed into the brain from the circulation, where they attack the damaging sticky plaque buildup that is a defining feature of Alzheimer’s disease. They are continuing to pursue this line of research in hopes of developing a next-generation drug for Alzheimer’s disease. This work, which has been funded by the National Institutes of Health, the Alzheimer’s Association, and the American Federation for Aging Research, has been published in numerous high-impact journals including Science, Nature Neuroscience,Immunity, PNAS, and The Journal of Neuroscience. Of the over 100 research papers that we have published, half have been related to Alzheimer’s disease. The Town lab has revolutionized the field of Alzheimer’s disease research by generating the first rat model of the disease that manifests all of the clinico-pathological hallmarks of the human syndrome. Specifically, they made transgenic rats that over-express two mutant human transgenes that are each independently causative of familial early-onset Alzheimer’s disease: “Swedish” mutant amyloid precursor protein and deltaE9 mutant presenilin-1. Unlike their transgenic mouse cousins that develop ‘senile’ plaques but fail to manifest ‘tangles’ and frank neuronal loss, these transgenic rats-for the first time-develop the full spectrum of Alzheimer pathologies. This makes them an invaluable tool for understanding Alzheimer’s disease etiology and for testing cutting-edge therapeutics pre-clinically. Using this exciting new Alzheimer rat, they are actively pursuing collaborations with academics and with industry around the world to understand basic mechanisms of Alzheimer’s and to develop a cure for this devastating neurodegenerative disease.

Ulmer Lab
Alzheimer and Related Diseases
Tobias Ulmer, PhD, associate professor of biochemistry and molecular biology, Zilkha Neurogenetic Institute

Fatal age-dependent neurodegenerative diseases such as prevalent Parkinson Disease (PD) encompass the toxic misfolding of the 140-residue protein α-synuclein (αS). These diseases limit the lifespan and quality of life of an increasing and embattling portion of the human population. To guide therapeutic courses of treatment, our long-term goal is to obtain vital understanding of the structure-function and structure-dysfunction relationship of αS. To understand the root cause of αS misfolding, we performed computational studies to simulate possible starting points of misfolding. To maintain physiological function of αS upon therapeutic intervention, its random coil to helix transition upon synaptic vesicle association needs to be preserved, requiring a detailed biophysical understanding of this event. We have used a range of biophysical tools to study this random coil to helix transition. By providing comprehensive, mechanistic insight into the αS folding and misfolding pathways, it will be possible to identify novel therapeutic avenues to combat αS-based neurodegeneration while preserving physiological function.

Zlokovic Lab
Alzheimer and Related Diseases
Berislav Zlokovic, MD, PhD, Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research, chair and professor of physiology and biophysics, Department of Physiology and Biophysics; director, Zilkha Neurogenetic Institute

The Zlokovic lab’s progress in preclinical studies in rodent models of ischemic stroke with 3K3AAPC, a 2nd generation cytoprotective-selective APC mutant with > 90% loss of anticoagulant activity, was translated in 2014 into Phase 2 multi-center clinical trial in stroke patients. Working with the neuroimaging group, they have developed a new improved test to evaluate cerebrovascular integrity and blood-brain barrier damage in the living human brain during normal aging and in individuals with mild cognitive impairment and multiple sclerosis. The lab has developed a new battery of assays to access simultaneously ~30 analytes in human and rodent biofluids (CSF, plasma) including biomarkers of different cell types within the neurovascular unit (e.g., endothelial cells, pericytes, astrocytes, olgo, neurons, inflammatory response, Abeta and tau). Next, they found that perivascular pericytes control progression of Alzheimer’s neurodegenerative like process in mice including accumulation of Abeta and tau and loss of neurons using models of Alzheimer’s disease with accelerated pericyte loss. They also showed that blood-brain barrier disruption is an early event that leads to motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis and that APC retards early motor neuron degeneration by preventing blood-brain barrier breakdown and eliminating neurotoxic microvascular lesions from the CNS. Two patents have been issued: one, for use of RAGE blockers to inhibit progression of Alzheimer’s pathology by blocking Abeta/RAGE interaction at the blood-brain barrier: and, second for uses of activated protein C analogs with reduced anticoagulant activity in neurological disorders and stroke.

Circuits

Chow Lab
Circuits
Robert Hsiu Ping Chow, MD, PhD, professor of physiology and biophysics, Zilkha Neurogenetic Institute

The Chow laboratory has started single-cell analysis of human spinal motor neurons of first and second trimester, correlating electrophysiology, morphology and gene transcription. This work, in the context of the NIH U01 (Chow and Knowles PIs), has paved the way for collaboration with Justin Ichida, assistant professor of stem cell biology and regenerative medicine, Department of Stem Cell Biology and Regenerative Medicine, (Broad/CIRM ) to investigate gene changes leading to spinal motor atrophy (SMA) and amyotrophic lateral sclerosis (ALS). The Chow lab has made major strides in understanding how genes normally associated with neuronal development also may play a major role in determining the invasion potential of cancer. The promising work may lead to a real-time rapid screen for cancer invasion potential and a novel treatment for highly invasive cancers. In collaboration with the Langen laboratory, the Chow lab has discovered a possible new mechanism by which plasticizers may increase type 2 diabetes mellitus and Alzheimer’s disease risk. Plasticizers had been thought to act largely as hormone disruptors. Our work suggests that plasticizers may play a role in damaging and/or killing pancreatic beta cells and neurons, by accelerating amyloid protein misfolding.

Sieburth Lab
Circuits
Derek Sieburth, PhD, associate professor of cell and neurobiology, Zilkha Neurogenetic Institute

The Sieburth lab is interested in how environmental cues impact behavior by influencing how neurons communicate with each other at specialized structures called synapses. They use the nematode as a model system for studying synapse structure and function because of its simple nervous system and the ability to visualize proteins in synapses in behaving animals. This year the lab discovered a new cellular signaling pathway that controls when neurons become activated during a rhythmic behavior. The lab also discovered that the neurotransmitter acetylcholine can act as a modulator of neuronal function by activating its receptor at sites far away from synapses. Finally, the lab showed that the amount of the synaptic protein neuroligin, which is implicated in autism, is controlled by a stress response pathway that functions in neurons to protect them from damage from oxidative stress.

Zhang Lab
Circuits
Li Zhang, PhD, associate professor of physiology and biophysics, Zilkha Neurogenetic Institute

The Zhang lab has made tremendous efforts in methodological innovation. In particular, they established high-quality in vivo whole-cell voltage-clamp recording techniques to reveal spectrotemporal interplays between excitation and inhibition in determining auditory processing functions of individual principal neurons. Further integrating two-photon imaging guided targeted patch-recordings from inhibitory neurons, neural circuit modeling, and optogenetic manipulations of neural activity of desired cell groups, we were able to derive local excitatory and inhibitory synaptic circuits underlying specific auditory computation. They have made substantial progress in understanding the synaptic circuit basis for auditory processing, along the following research directions: a) specific and sequential laminar processing in each layer of the primary auditory cortex; b) processing of unique features of acoustic signals at several major subcortical auditory nuclei; c) postnatal development of functional synaptic circuits in the auditory cortex. For example, on cortical laminar processing, their series of studies revealed that differential excitatory/inhibitory interplays in terms of spectral, temporal and amplitopic relationships, which are inherited from variations of local circuits all recruiting a feedforward inhibitory circuit module, lead to differential laminar processing.

Genomics

Conti Lab
Genomics
David Conti, PhD, professor of preventive medicine in the division of biostatistics, Department of Preventive Medicine

The Conti lab has made several advances in statistical methodology for the integration of biological information in genetic association studies via the use of Bayesian stochastic search. In particular, they have developed an integrative Bayesian model uncertainty (iBMU) method, which formally incorporates multiple sources of data via a second-stage probit model on the probability that any predictor is associated with the outcome of interest. Using simulations, they demonstrate that iBMU leads to an increase in power to detect true marginal associations over more commonly used variable selection techniques, such as least absolute shrinkage and selection operator and elastic net. The increase in power and efficiency of their method becomes more substantial as the predictor-level covariates become more informative. In addition, the Conti lab has created a scalable algorithm called PEAK that improves the efficiency of MCMC by dividing a large set of variables into related groups using a rooted graph. Their algorithm takes advantage of parallel computing and existing biological databases when available.

Hearing/Ear

Kalluri Lab
Hearing/Ear
Radha Kalluri, PhD, assistant professor of otolaryngology and biomedical engineering, Department of Otolaryngology – Head and Neck Surgery

Projects in the lab are combining in vitro patch clamp experiments, with anatomy, and computational modelling to study the biophysical basis for sensory signaling in the vestibular and auditory sensory systems. In the past year, the Kalluri lab has been working on determining if the intrinsic biophysical properties of auditory and vestibular sensory neurons contribute to functionally distinct sub-classes. They’ve recently identified groups of ion channels that may differ between functionally distinct groups of vestibular and auditory neurons. They’ve developed a computational model that tests the impact of these ion channel groups on neuronal function.

Ohyama Lab
Hearing/Ear
Takahiro Ohyama, PhD, assistant professor of research otolaryngology, Department of Otolaryngology – Head and Neck Surgery

The Ohyama Lab is investigating how the cochlea, the auditory organ, develops during embryonic development. They discovered BMP signaling pathway is important for cell fate decision between sensory and non-sensory structure of mammalian cochlea. The Ohyama lab is also analyzing the mechanisms how migrating neural crest cells are incorporated into the non-sensory structure of developing cochlea, which is crucial for proper hearing functions. These projects aim to understand disease mechanisms of hearing impairment and develop translational resear

Psychiatric Genetics

Bonnin Lab
Psychiatric Genetics
Alex Bonnin, PhD, assistant professor of cell and neurobiology, Zilkha Neurogenetic Institute

The research done by the Bonnin Lab over the past year has demonstrated that exposure to bacterial and viral-like immunostimulants in pregnant mice trigger different maternal and placental inflammatory responses, which induce a rapid increase of tryptophan metabolic gene expression and enzyme activity specifically in the placenta. Most importantly, this translates into rapid, differential alterations of critical neuroactive molecules, such as serotonin, in the fetal brain. These effects are likely to result in compromised serotonergic modulation of fetal brain development and have direct, long-term consequences on fetal brain circuit formation and postnatal brain function. The progress made last year, soon to be reported in a manuscript, provides strong support to the hypothesis that alteration of placental tryptophan metabolism by maternal inflammation during early gestation constitutes a new molecular pathway for the fetal programming of neurodevelopmental disorders such as autism or schizophrenia. In addition, the lab’s prenatal toxico-pharmacological exposure studies reveal unexpected, and potentially beneficial, effects of antidepressant drugs on fetal brain development, in the context of underlying maternal gestational stress. Finally, with Jennifer King, LAC+USC maternal-fetal medicine fellow, the lab has started to explore a new, long-range, molecular communication pathway between the placenta and the fetal brain. Preliminary results are encouraging and may lead to future identification of new targets and biomarkers for the fetal programming of mental disorders.

Coba Lab
Psychiatric Genetics
Marcelo Coba, PhD, assistant professor of psychiatry and the behavioral sciences, Department of Psychiatry and the Behavioral Sciences

Many of the genes that have been implicated as risk factors for the psychiatric disorders are thought to affect the function of neuronal synapses. The Coba lab is interested to understand the molecular mechanisms linking psychiatric disease candidate genes to synaptic signaling. This year they made significant progress in the understanding of how synaptic signaling processes relates to psychiatric disease. Using Mass spectrometry, bioinformatics and mouse genetics, the lab determined the composition of different synaptic complexes, mapping more than 2,500 in-vivo protein interactions in mouse pre-frontal cortex. They determined that these synaptic complexes were enriched in Schizophrenia candidate risk factors and that disruption of core components of these complexes, regulates the composition and association of proteins by impairment of protein-protein interactions. They also determined that a cluster of proteins related to psychiatric disease, associates in protein complexes that modulates hiPSC proliferation, and differentiation. These complexes are not functionally related to synaptic molecules and might function as an independent cluster for psychiatric disease risk.

Vascular

Mack Lab
Vascular
William Mack, MD, associate professor of neurological surgery (clinical scholar), Department of Neurological Surgery and director of the Cerebrovascular Laboratory, Zilkha Neurogenetic Institute

The Mack laboratory was awarded a grant to study the effects of air pollution from vehicular exhaust in the setting of acute stroke. Pilot studies demonstrated a detrimental effect of particulate matter on stroke progression. They published a paper characterizing the role of the C5 complement component in the setting of chronic cerebral hypoperfusion secondary to carotid artery stenosis. Along with our collaborators, they published several studies dissecting the genetic/ epigenetic characteristics of malignant meningiomas.

Peti-Peterdi Lab
Vascular
Janos Peti-Peterdi, MD, PhD, professor of physiology and biophysics, Zilkha Neurogenetic Institute

The Peti-Peterdi lab investigated the cellular and molecular mechanisms of glomerular kidney diseases, and identified several new potential therapeutic targets for future further development. The main focus of their studies last year was the role of podocytes, a unique pericyte-like cell type within the glomerulus, in the development of glomerulosclerosis and chronic kidney disease. They identified purinergic calcium signaling mediated by the P2Y2 receptor, as the most significant mechanism of podocyte cell-to-cell communication and propagation of podocyte injury. They showed that mouse models deficient in P2Y2 were protected from the development of proteinuria. The lab also showed, for the first time, direct visual evidence for the generation of new podocytes in the intact living mouse kidney, using a new technical innovation, serial multiphoton microscopy. They tracked the origin and fate of individually marked podocytes and resident renal mesenchymal stem cells within the living kidney using this technology. The pattern of cell migrations gave the Peti-Peterdi lab new visual clues on novel mechanisms of glomerular and renal tissue remodeling and regeneration. They are currently in the process of exploring these new mechanisms further.

Vision/Eye

Chen Lab
Vision/Eye
Jeannie Chen, PhD, professor of cell and neurobiology, Zilkha Neurogenetic Institute

Excessive light exposure is known to harm the retina and exacerbates disease progression in many retinal disorders, including age-related retinal degeneration. How light exerts its harmful effect on the retina is not well understood. The first step in one’s nighttime vision begins with photon absorption by rhodopsin, which then activates many transducin molecules. Transducin, in turn, stimulates phosphodiesterase enzyme activity to breakdown cGMP. At the plasma membrane of the rod cell, the fall in cGMP concentration causes cGMP-gated channels close, which then block the flow of ion currents into the cell. In this manner photon absorption ultimately leads to a change in current at the plasma membrane in a process called the phototransduction cascade. An over-active phototransduction cascade is known to cause retinal degeneration. During the past year, the Chen Lab showed that excessive activation of transducin, but not closure of the cGMP-gated channels, causes photoreceptor cell death by induction of the unfolded protein response. These findings provide a target for therapeutic intervention in certain retinal disorders caused by constitutive phototransduction.

Tao Lab
Vision/Eye
Huizhong Tao, PhD, associate professor of cell and neurobiology, Zilkha Neurogenetic Institute

The Tao lab made three major discoveries. First, in layer 4 of the mouse visual cortex they revealed synaptic changes induced by monocular deprivation (MD), which is a popular experimental model for studying mechanisms and treatments for amblyopia. While confirming a long-time suspicion of decreased excitatory inputs from the deprived eye, their results also generate novel insights into the expression mechanism for MD-induced cortical plasticity by demonstrating that a MD-induced general down-regulation of inhibitory inputs contributes to the increased responsiveness through the non-deprived eye. Second, by combining optogenetic techniques in specific transgenic mouse lines with intracellular voltageclamp recordings, they found that recurrent intracortical excitatory circuits play an important role in amplifying the orientation-tuned signal relayed by the visual thalamus, while keep the overall orientation tuning preserved. This finding shed light on the organization of cortical circuits to produce sharp orientation selectivity in visual cortex. Third, they examined synaptic mechanisms underlying direction selectivity in layer 4 of the primary visual cortex. They found that direction selectivity originates from direction-tuned thalamic input, but is greatly sharpened by untuned inhibitory inputs coming from non-direction- selective fast-spiking inhibitory neurons, a major inhibitory cell type. Interestingly, the direction tuning of synaptic inputs is highly correlated with their asymmetry in spatial distribution of synaptic amplitudes. Ongoing experiments are aimed at understanding how spatial asymmetric can results in a directional bias of synaptic responses to moving stimuli.