Hope Center for Neurological Disorders

St. Louis, MO, United States

Hope Center for Neurological Disorders

St. Louis, MO, United States
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Bennett R.E.,Hope Center for Neurological Disorders | Mac Donald C.L.,Hope Center for Neurological Disorders | Brody D.L.,Hope Center for Neurological Disorders
Neuroscience Letters | Year: 2012

Mild traumatic brain injuries (TBI) are common in athletes, military personnel, and the elderly, and increasing evidence indicates that these injuries have long-term health effects. However, the difficulty in detecting these mild injuries in vivo is a significant impediment to understanding the underlying pathology and treating mild TBI. In the following experiments, we present the results of diffusion tensor imaging (DTI) and histological analysis of a model of mild repetitive closed-skull brain injury in mouse. Histological markers used included silver staining and amyloid precursor protein (APP) immunohistochemistry to detect axonal injury, and Iba-1 immunohistochemistry to assess microglial activation. At 24. h post-injury, before silver staining or microglial abnormalities were apparent by histology, no significant changes in any of the DTI parameters were observed within white matter. At 7 days post-injury we observed a reduction in axial and mean diffusivity. Relative anisotropy at 7 days correlated strongly with the degree of silver staining. Interestingly, APP was not observed at any timepoint examined. In addition to the white matter alterations, mean diffusivity was elevated in ipsilateral cortex at 24. h but returned to sham levels by 7 days. Altogether, this demonstrates that DTI is a sensitive method for detecting axonal injury despite a lack of conventional APP pathology. Further, this reflects a need to better understand the histological basis for DTI signal changes in mild TBI. © 2012 Elsevier Ireland Ltd.


DeVos S.L.,Hope Center for Neurological Disorders | Goncharoff D.K.,Hope Center for Neurological Disorders | Chen G.,Hope Center for Neurological Disorders | Kebodeaux C.S.,Hope Center for Neurological Disorders | And 12 more authors.
Journal of Neuroscience | Year: 2013

Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS-brain and spinal cord tissue, interstitial fluid, and CSF-while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability. © 2013 the authors.


Valakh V.,Hope Center for Neurological Disorders | Walker L.J.,Hope Center for Neurological Disorders | Skeath J.B.,University of Washington | DiAntonio A.,Hope Center for Neurological Disorders
Journal of Neuroscience | Year: 2013

The MAPKKK dual leucine zipper-containing kinase (DLK, Wallenda in Drosophila) is an evolutionarily conserved component of the axonal injury response pathway. After nerve injury,DLKpromotes degeneration of distal axons and regeneration of proximal axons. This dual role in coordinating degeneration and regeneration suggests that DLK may be a sensor of axon injury, and so understanding how DLK is activated is important. Two mechanisms are known to activate DLK. First, increasing the levels of DLK via overexpression or loss of thePHRubiquitin ligases that target DLK activate DLK signaling. Second, in Caenorhabditis elegans, a calcium-dependent mechanism, can activate DLK. Here we describe a new mechanism that activates DLK in Drosophila: Loss of the spectraplakin short stop (shot). In a genetic screen for mutants with defective neuromuscular junction development, we identify a hypomorphic allele of shot that displays synaptic terminal overgrowth and a precocious regenerative response to nerve injury. We demonstrate that both phenotypes are the result of overactivation of the DLK signaling pathway. Wefurther show that, unlike mutations in the PHR ligase Highwire, loss of function of shot activates DLK without a concomitant increase in the levels of DLK. As a spectraplakin, Shot binds to both actin and microtubules and promotes cytoskeletal stability. The DLK pathway is also activated by downregulation of the TCP1 chaperonin complex, whose normal function is to promote cytoskeletal stability. These findings support the model that DLK is activated by cytoskeletal instability, which is a shared feature of both spectraplakin mutants and injured axons. © 2013 the authors.


News Article | October 27, 2016
Site: www.eurekalert.org

Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells' ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body's energy supply chain is a key driver of the aging process. Now, scientists at Washington University School of Medicine in St. Louis have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity. The study is published Oct. 27 in the journal Cell Metabolism. "We have shown a way to slow the physiologic decline that we see in aging mice," said Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine. "This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age." Imai is working with researchers conducting a clinical trial to test the safety of NMN in healthy people. The phase 1 trial began earlier this year at Keio University School of Medicine in Tokyo. With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work by Imai and co-senior author Jun Yoshino, MD, PhD, an assistant professor of medicine, has shown that NAD levels decrease in multiple tissues as mice age. Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide). NMN can be given safely to mice and is found naturally in a number of foods, including broccoli, cabbage, cucumber, edamame and avocado. The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues. "We wanted to make sure that when we give NMN through drinking water, it actually goes into the blood circulation and into tissues," Imai said. "Our data show that NMN absorption happens very rapidly." To determine the long-term effects of giving NMN, Imai, Yoshino and their colleagues studied three groups of healthy male mice fed regular mouse chow diets. Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN. The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years. The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice. "When we give NMN to the young mice, they do not become healthier young mice," Yoshino said. "NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body's ability to make NMN and, by extension, NAD." In skeletal muscle, the investigators -- including the study's first author, Kathryn Mills, the research supervisor in Imai's lab -- found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants. They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity. The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight. In a paper published earlier this year in Cell Reports, Yoshino and his colleagues revealed more details of how NAD works in influencing glucose metabolism and the body's fat tissue. In that study, the mice had a defect in the ability to manufacture NAD only in the body's fat tissue. The rest of their tissues and organs were normal. "Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids," Yoshino said. "When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism." Added Imai, "This is important because Jun showed that if you mess up NAD synthesis only in fat tissue, you see insulin resistance everywhere. Adipose tissue must be doing something remarkable to control whole body insulin sensitivity." During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration. "Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence," Imai said. "But we have not seen any differences in cancer rates between the groups." The phase 1 trial in Japan is using NMN manufactured by Oriental Yeast Co., which also provided the NMN used in these mouse studies. Outside of this clinical trial, high-grade NMN for human consumption is not commercially available. But there's always broccoli. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai S. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism. Oct. 27, 2016. This work was supported by the National Institutes of Health (NIH), grant numbers P30 DK020579 and P30 DK56341; a Research to Prevent Blindness Physician Scientist Award; a Research to Prevent Blindness Unrestricted Grant to the Department of Ophthalmology; the Hope Center for Neurological Disorders at Washington University; the UK Research Councils; and Biotechnology and Biological Science Research Council. This work was conducted under a sponsored research agreement between Washington University and Oriental Yeast Co. Stromsdorfer KL, Yamaguchi S, Yoon MJ, Moseley AC, Franczyk MP, Kelly SC, Qi N, Imai S, Yoshino J. NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Reports. Aug. 4, 2016. This work was supported by the National Institutes of Health (NIH), grant numbers DK56341, DK37948, DK20579, DK52574, UL1 TR000450, DK104995, AG024150, AG037457, DK089503, DK020572; a Central Society for Clinical and Translational Research Early Career Development Award; the Longer Life Foundation; and the Sumitomo Life Welfare and Culture Foundation. Imai is a co-founder of Metro Midwest Biotech, whose technology was evaluated in this Cell Reports paper. Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.


News Article | September 14, 2016
Site: www.biosciencetechnology.com

Washington University School of Medicine in St. Louis will collaborate with the pharmaceutical companies AbbVie, Biogen, and Eli Lilly & Co. to investigate the buildup and clearance of tau protein in the brains of patients with Alzheimer’s disease. Tau is abundant in the brain’s nerve cells, where it stabilizes the scaffold-like microtubules that play a critical role in transporting cargo within cells. But in Alzheimer’s disease as well as other “tauopathies,” such as progressive supranuclear palsy and frontotemporal dementia, clumps of tau protein are abnormally deposited in nerve cells in tangles. However, it remains unclear how tau clumps relate to the memory loss and cognitive decline seen in patients with Alzheimer’s, or how they correspond to the brain’s accumulation of amyloid beta, another hallmark of the disease. The newly formed collaboration, called the tau SILK Consortium, will take advantage of a technique developed by Washington University colleagues Randall Bateman, M.D., Chihiro Sato, Ph.D., and Nico Barthelemy, Ph.D., to monitor alterations in the rate at which tau is produced, released and cleared from the brain and its surrounding fluid in patients with Alzheimer’s disease. The technique, called SILK (for Stable Isotope Labeling Kinetics) has been used to measure levels of amyloid beta production and clearance in spinal fluid. Such research has revealed that patients with Alzheimer’s have altered production and clearance of amyloid beta decades before symptoms of the disease become apparent. “We will determine if and how rates of tau production and clearance are altered in Alzheimer’s disease, which will provide essential information on how to design trials for Alzheimer’s disease and assist in the development of potential treatments that target tau,” said Bateman, the principle investigator of the tau SILK Consortium. As part of the collaboration, Washington University, AbbVie, Biogen and Eli Lilly & Co. will conduct a study that uses imaging tracers that can bind to tau tangles in the brain. The researchers want to learn whether the abnormal tau aggregation in Alzheimer’s disease is the result of increased tau production or decreased tau clearance, or a combination of both. They also will investigate whether a specific form of tau is more likely to accumulate than other forms. The ultimate goal is to better understand tau kinetics, a line of investigation that can inspire development of potential therapies for treating Alzheimer’s disease and other tauopathies. The tau SILK Consortium is coordinated by the Hope Center for Neurological Disorders at Washington University.


Zaidman C.M.,University of Washington | Harms M.B.,University of Washington | Harms M.B.,Hope Center for Neurological Disorders | Pestronk A.,University of Washington
Journal of Neurology | Year: 2013

We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited [Charcot-Marie-Tooth-1 (CMT-1) (n = 35)] and acquired [chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 55), Guillaine-Barre syndrome (GBS) (n = 21) and multifocal motor neuropathy (MMN) (n = 17)] demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none, no enlargement; mild, nerves enlarged but never more than twice normal; regional, nerves normal in at least one region and enlarged more than twice normal in at least one region; diffuse, nerves enlarged at all four regions with at least one region more than twice normal size. Nerve enlargement was commonly diffuse (89 %) and generally more than twice normal size in CMT-1, but not (p < 0.001) in acquired disorders which mostly had either no, mild or regional nerve enlargement [CIDP (64 %), GBS (95 %), and MMN (100 %)]. In CIDP, subjects treated within 3 months of disease onset had less nerve enlargement than those treated later. Ultrasound identified patterns of diffuse nerve enlargement can be used to screen patients suspected of having CMT-1. Normal, mildly, or regionally enlarged nerves in demyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. © 2013 Springer-Verlag Berlin Heidelberg.


Klemenhagen K.C.,University of Washington | O'Brien S.P.,University of Washington | Brody D.L.,University of Washington | Brody D.L.,Hope Center for Neurological Disorders
PLoS ONE | Year: 2013

The debilitating effects of repetitive concussive traumatic brain injury (rcTBI) have been increasingly recognized in both military and civilian populations. rcTBI may result in significant neurological, cognitive, and affective sequelae, and is often followed by physical and/or psychological post-injury stressors that may exacerbate the effects of the injury and prolong the recovery period for injured patients. However, the consequences of post-injury stressors and their subsequent effects on social and emotional behavior in the context of rcTBI have been relatively little studied in animal models. Here, we use a mouse model of rcTBI with two closed-skull blunt impacts 24 hours apart and social and emotional behavior testing to examine the consequences of a stressor (foot shock fear conditioning) following brain injury (rcTBI). rcTBI alone did not affect cued or contextual fear conditioning or extinction compared to uninjured sham animals. In the sucrose preference test, rcTBI animals had decreased preference for sucrose, an anhedonia-like behavior, regardless of whether they experienced foot shock stress or were non-shocked controls. However, rcTBI and post-injury foot shock stress had synergistic effects in tests of social recognition and depression-like behavior. In the social recognition test, animals with both injury and shock were more impaired than either non-shocked injured mice or shocked but uninjured mice. In the tail suspension test, injured mice had increased depression-like behavior compared with uninjured mice, and shock stress worsened the depression-like behavior only in the injured mice with no effect in the uninjured mice. These results provide a model of subtle emotional behavioral deficits after combined concussive brain injury and stress, and may provide a platform for testing treatment and prevention strategies for social behavior deficits and mood disorders that are tailored to patients with traumatic brain injury. © 2013 Klemenhagen et al.


Gerdts J.,Washington University Medical School | Brace E.J.,Washington University Medical School | Sasaki Y.,Washington University Medical School | DiAntonio A.,Washington University Medical School | And 3 more authors.
Science | Year: 2015

Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD+) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD+, whereas SARM1-induced axon destruction could be counteracted by increased NAD+ synthesis. SARM1-induced depletion of NAD+ may explain the potent axon protection in Wallerian degeneration slow (Wlds) mutant mice.


Fuentealba R.A.,Hope Center for Neurological Disorders | Marasa J.,University of Washington | Diamond M.I.,Hope Center for Neurological Disorders | Piwnica-Worms D.,University of Washington | Weihl C.C.,Hope Center for Neurological Disorders
Human Molecular Genetics | Year: 2012

Intracellular protein aggregation is a common pathologic feature in neurodegenerative diseases such as Huntington' disease, amyotrophic lateral sclerosis and Parkinson' disease. Although progress towards understanding protein aggregation in vitro has been made, little of this knowledge has translated to patient therapy. Moreover, mechanisms controlling aggregate formation and catabolism in cellulo remain poorly understood. One limitation is the lack of tools to quantitatively monitor protein aggregation and disaggregation. Here, we developed a protein-aggregation reporter that uses huntingtin exon 1 containing 72 glutamines fused to the N-terminal end of firefly luciferase (httQ72-Luc). httQ72-Luc fails to aggregate unless seeded by a non-luciferase-containing polyglutamine (polyQ) protein such as Q80-cfp. Upon co-aggregation, httQ72-luc becomes insoluble and loses its enzymatic activity. Using httQ72-Luc with Q80(CFP/YFP) as seeds, we screened the Johns Hopkins Clinical Compound Library and identified leflunomide, a dihydroorotate dehydrogenase inhibitor with immunosuppressive and anti-psoriatic activities, as a novel drug that prevents polyQ aggregation. Leflunomide and its active metabolite teriflunomide inhibited protein aggregation independently of their known role in pyrimidine biosynthesis, since neither uridine treatment nor other pyrimidine biosynthesis inhibitors affected polyQ aggregation. Inducible cell line and cycloheximide-chase experiments indicate that these drugs prevent incorporation of expanded polyQ into an aggregate. This study demonstrates the usefulness of luciferase-based protein aggregate reporters for high-throughput screening applications. As current trials are under-way for teriflunomide in the treatment of multiple sclerosis, we propose that this drug be considered a possible therapeutic agent for polyQ diseases. © The Author 2011. Published by Oxford University Press. All rights reserved.


Holmes B.B.,Hope Center for Neurological Disorders | Furman J.L.,Hope Center for Neurological Disorders | Mahan T.E.,Hope Center for Neurological Disorders | Yamasaki T.R.,Hope Center for Neurological Disorders | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration. © 2014, National Academy of Sciences. All rights reserved.

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