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Jianxue Li,
Xuesong Gu,
Yinghua Ma,
Monica L Calicchio,
Dong Kong,
Yang D Teng,
Lili Yu,
Andrew M Crain, Timothy K Vartanian,
Renata Pasqualini,
Wadih Arap,
Towia A Libermann,
Evan Y Snyder,
Richard L Sidman
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ABSTRACT: The molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The Purkinje cell degeneration (pcd) mutant mouse is characterized by mutations in Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal pcd(Sid) mice and linked this deficit to a deletion mutation in exon 7 of Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to Nna1 underlying abnormal Purkinje cell dendritogenesis in pcd(Sid) mice. We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable.
Neuron 10/2010; 68(1):45-60. · 14.74 Impact Factor
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ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)(G93A) transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1(G93A) spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRbeta deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1(G93A) (TCRbeta-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.
Proceedings of the National Academy of Sciences 12/2008; 105(46):17913-8. · 9.68 Impact Factor
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ABSTRACT: Mounting a humoral response to foreign proteins is a normal function of immunity, but an undesirable outcome for protein-based therapeutic biologics. "Neutralizing antibodies" (NAbs) is the term given for antibodies against a biologic that reduce its bioavailability. Biologic therapeutics used to treat patients with multiple sclerosis (MS) have been associated with the risk of seroconversion to neutralizing antibody-positive status. Therefore, it is important to understand the causes of immunogenicity, methods for assessing antibody status, and the clinical impact of NAbs, particularly in patients who appear to be nonresponsive to treatment.
Factors such as protein structure, contaminants, administration route, and patient characteristics affect immunogenicity of biologics used to treat MS. Binding assays and bioassays can be used for the detection and quantification of NAbs to these agents. Clinical studies have demonstrated that NAbs to interferon beta therapy develop between 3 and 18 months after treatment initiation, and their presence affects treatment efficacy on clinical, imaging, and immunologic parameters. Binding antibodies to glatiramer acetate have been detected, but the clinical significance of these antibodies remains unclear. NAbs to natalizumab have also been identified and appear to at least partially abrogate the therapeutic response.
When considering treatment options for patients with MS, the development of NAbs and their effects on clinical efficacy should be considered. Standardization of antibody assays and the development of guidelines for the management of patients with NAbs are important areas of future research.
The Neurologist 12/2007; 13(6):355-62. · 1.26 Impact Factor
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ABSTRACT: The myelin sheath can be compared to the neuronal growth cone in that the unfurled sheath looks like a giant lamellum. The authors recently tested this hypothesis by examining the importance of WAVE1, a regulator of lamellipodia formation in neurons and other cells, in myelinogenesis. They found that WAVE1 is critical for formation of oligodendrocyte lamellae and myelin sheaths. They review the regulation of WAVE1 and how WAVE1 is transported and localized to lamellipodia. Because they found that some but not all myelination was impaired by knockout of WAVE1 function, they hypothesize that other regulators of actin nucleation help oligodendrocytes produce myelin in parallel with WAVE1 function. Interestingly, they found that oligodendrocyte maturation also is disturbed with WAVE1 knockout and propose that proper localization and transport of signaling molecules relevant to the integrin signaling cascade are disrupted by loss of WAVE1 function.
The Neuroscientist 11/2007; 13(5):486-91. · 4.57 Impact Factor
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ABSTRACT: A product of myosin Va mutations, Griscelli's syndrome type 1 (GS1) is characterized by several neurologic deficits including quadraparesis, mental retardation, and seizures. Although multiple studies have not clearly established a cause for the neurologic deficits linked with GS1, a few reports suggest that GS1 is associated with abnormal myelination, which could cause the neurologic deficits seen with GS1. In this report, we investigate whether myosin Va is critical to oligodendrocyte morphology and to myelination in vivo. We found that myosin Va-null mice exhibit significantly impaired myelination of the brain, optic nerve, and spinal cord. Oligodendrocytes express myosin Va and loss of myosin Va function resulted in significantly smaller lamellas and decreased process number, length, and branching of oligodendrocytes. Loss of myosin Va function also blocked distal localization of vesicle-associated membrane protein 2 (VAMP2), which is known to associate with myosin Va. When VAMP2 function was disrupted, oligodendrocytes exhibited similar morphologic deficits to what is seen with functional ablation of myosin Va. Our findings establish a role for both myosin Va and VAMP2 in oligodendrocyte function as it relates to myelination.
Journal of Neuroscience 11/2007; 27(42):11366-75. · 7.11 Impact Factor
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ABSTRACT: Purkinje neurons (PNs), the central cells in cerebellar circuitry and function, constitute a vulnerable population in many human genetic, malignant, hypoxic, and toxic diseases. In the nervous (nr) mutant mouse, the majority of PNs die in the fourth to fifth postnatal weeks, but the responsible molecules are unknown. We first disclose a remarkable increase in mRNA expression and protein concentration in the nr cerebellum of tissue plasminogen activator (tPA), a gene closely linked to the mapped but as-yet-uncloned nr locus. Evidence that excessive tPA triggers nr PN death was obtained with organotypic slice cultures expressing the nr PN phenotype, in which an inhibitor of tPA led to increased nr PN survival. An antagonist of protein kinase C, a downstream component in the tPA pathway, also increased nr PN survival. Additional downstream targets in the tPA pathway (the mitochondrial voltage-dependent anion channel, brain-derived neurotrophic factor, and neurotrophin 3) were also abnormal, in parallel with the alterations in PN mitochondrial morphology, dendritic growth, and synaptogenesis that culminate in nr PN death and motor incoordination. We thus propose a molecular pathway by which the excessive tPA in nr cerebellum mediates PN degeneration.
Proceedings of the National Academy of Sciences 06/2006; 103(20):7847-52. · 9.68 Impact Factor
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ABSTRACT: Myelin formation involves the outgrowth of an oligodendrocyte cell process that can be regarded as a giant lamellipodium because it is an actively growing structure with extruded cytoplasm. The actin cytoskeleton is critical to morphogenesis, but little is known about regulation of actin dynamics in oligodendrocytes. Wiskott-Aldrich syndrome protein family verprolin homologous (WAVE) proteins mediate lamellipodia formation; thus, we asked whether these proteins function in oligodendrocyte process formation and myelination. Here, we show that WAVE1 is expressed by oligodendrocytes and localizes to the lamella leading edge where actin polymerization is actively regulated. CNS WAVE1 expression increases at the onset of myelination. Expression of dominant-negative WAVE1 impaired process outgrowth and lamellipodia formation in cultured oligodendrocytes. Similarly, oligodendrocytes isolated from mice lacking WAVE1 had fewer processes compared with controls, whereas neurons and astrocytes exhibited normal morphology. In white matter of WAVE1-/- mice, we found regional hypomyelination in the corpus callosum and to a lesser extent in the optic nerve. In optic nerve from WAVE1-/- mice, there were fewer nodes of Ranvier but nodal morphology was normal, implicating a defect in myelin formation. Our in vitro findings support a developmentally dynamic and cell-autonomous role for WAVE1 in regulating process formation in oligodendrocytes. Additionally, WAVE1 function during CNS myelination appears to be linked to regional cues. Although its loss can be compensated for in many CNS regions, WAVE1 is clearly required for normal amounts of myelin to form in corpus callosum and optic nerve. Together, these data demonstrate a role for WAVE1 in oligodendrocyte morphogenesis and myelination.
Journal of Neuroscience 06/2006; 26(21):5849-59. · 7.11 Impact Factor
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ABSTRACT: To evaluate techniques for anatomical and physiological imaging of the intracranial optic nerve (ON), optic chiasm (OC), and optic tract (OT) at 3T with the aim of visualizing axonal damage in multiple sclerosis (MS).
Imaging was performed on a 3T scanner employing a custom-designed head coil that consisted of a coil array with four coils (30 x 30 cm(2)). Oblique fast spin echo (FSE) images, magnetization transfer (MT)-enhanced 3D gradient-echo (GRE) time-of-flight (TOF) images, and line scan diffusion images (LSDI) were obtained. Full diffusion tensor (DT) analysis was performed, and apparent diffusion coefficient (ADC), fractional anisotropy (FA), and fiber direction maps were obtained.
FSE anatomic images were obtained with an in-plane resolution of 0.39 x 0.52 mm(2). The in-plane resolution of the MT and LSDI images was 0.78 x 0.78 mm(2). The OC, intracranial ON, and OT can be seen on these images. The dominant fiber orientations in the OC, ON, and OT, as derived from the DT images, are displayed.
This study shows that by using 3T and a custom-designed, four-channel head coil, it is possible to acquire high-resolution anatomical and physiological images of the OC, ON, and OT. The pilot results presented here pave the way for imaging the anterior visual pathway in patients with MS.
Journal of Magnetic Resonance Imaging 09/2005; 22(2):302-6. · 2.70 Impact Factor
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ABSTRACT: Protein- and peptide-based disease-modifying agents for multiple sclerosis (MS), including interferon beta (IFNbeta) and glatiramer acetate (GA), have been associated with the formation of antibodies. Neutralizing antibodies (NAbs) block or neutralize the biological effects of the protein or polypeptide, potentially decreasing the therapeutic effects of these agents. Although the clinical relevance of antibodies against GA requires further investigation; both the incidence of NAbs to the three IFNbeta products (IFNbeta1b-Betaseron, IFNbeta1a-Rebif, and IFNbeta1a-Avonex) and the clinical relevance are quite clear. Data from clinical trials of IFNbeta products show that the immunogenicity of Betaseron > Rebif > Avonex and persistent NAbs reduce the clinical efficacy of IFNbeta. Because the initial detection of NAbs in the serum of patients receiving IFNbeta usually occurs between 6 and 15 months and appears to precede any apparent reduction in clinical efficacy by approximately 6 to 12 months, trials with a duration of less than 3 years are problematic when the clinical impact of NAbs is assessed. The potential development of NAbs is an important consideration in selection and monitoring treatment of MS. Long-term prospective studies are needed to further define the clinical effects of NAbs on patients receiving disease-modifying therapies for MS.
Neurology 12/2004; 63(11 Suppl 5):S42-9. · 8.31 Impact Factor
