Browsing by Subject "Amyotrophic Lateral Sclerosis"

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    Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis
    (Nature Publishing Group, 2015-11-20) Fontanilla, Christine V.; Gu, Huiying; Liu, Qingpeng; Zhu, Timothy Z.; Johnstone, Brian H.; March, Keith L.; Pascuzzi, Robert M.; Farlow, Martin R.; Du, Yansheng; Department of Neurology, IU School of Medicine
    Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1(G93A)). Treating symptomatic SOD1(G93A) mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1(G93A) mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1(G93A) mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1(G93A) mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1(G93A) mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.
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    Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease
    (The American Association of Immunologists, 2018-07-01) Sun, Kevin; Li, Xiao; Chen, Xing; Bai, Ying; Zhou, Gao; Kokiko-Cochran, Olga N.; Lamb, Bruce; Hamilton, Thomas A.; Lin, Ching-Yi; Lee, Yu-Shang; Herjan, Tomasz; Neuroscience, IU School of Medicine
    Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.
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    Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update
    (Springer, 2009-11-19) Mackenzie, Ian R. A.; Neumann, Manuela; Bigio, Eileen H.; Cairns, Nigel J.; Alafuzoff, Irina; Kril, Jillian; Kovacs, Gabor G.; Ghetti, Bernardino; Halliday, Glenda; Holm, Ida E.; Ince, Paul G.; Kamphorst, Wouter; Revesz, Tamas; Rozemuller, Annemieke J. M.; Kumar-Singh, Samir; Akiyama, Haruhiko; Baborie, Atik; Spina, Salvatore; Dickson, Dennis W.; Trojanowski, John Q.; Mann, David M. A.; Pathology and Laboratory Medicine, School of Medicine
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    The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43
    (PLoS, 2014-12-04) Liachko, Nicole F.; McMillan, Pamela J.; Strovas, Timothy J.; Loomis, Elaine; Greenup, Lynne; Murrell, Jill R.; Ghetti, Bernardino; Raskind, Murray A.; Montine, Thomas J.; Bird, Thomas D.; Leverenz, James B.; Kraemer, Brian C.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups of neurodegenerative disease. Kinase hyperactivity may be a consistent feature of ALS and FTLD-TDP, as phosphorylated TDP-43 is not observed in the absence of neurodegeneration. By examining changes in TDP-43 phosphorylation state, we have identified kinases controlling TDP-43 phosphorylation in a C. elegans model of ALS. In this kinome-wide survey, we identified homologs of the tau tubulin kinases 1 and 2 (TTBK1 and TTBK2), which were also identified in a prior screen for kinase modifiers of TDP-43 behavioral phenotypes. Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. Furthermore, protein levels of TTBK1 and TTBK2 are increased in frontal cortex of FTLD-TDP patients, and TTBK1 and TTBK2 co-localize with TDP-43 inclusions in ALS spinal cord. These kinases may represent attractive targets for therapeutic intervention for TDP-43 proteinopathies such as ALS and FTLD-TDP.