Centre for Neuroscience - Research Publications
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ItemGas6 Increases Myelination by Oligodendrocytes and Its Deficiency Delays Recovery following Cuprizone-Induced Demyelination(PUBLIC LIBRARY SCIENCE, 2011-03-10)Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.
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ItemOptic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes(PUBLIC LIBRARY SCIENCE, 2013-12-26)BACKGROUND: Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). OBJECTIVES: To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. METHODS: Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. RESULTS: Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. CONCLUSIONS: These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
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ItemOptic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes(PUBLIC LIBRARY SCIENCE, 2012-12-18)Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = -9.24%, p = 0.01), 6 months (mean = -12.48%, p<0.0001) and 12 months (mean = -7.61%, p = 0.003). Greater reduction in MTR at 3 months in patients was associated with subsequent loss of high contrast letter acuity at 6 (ρ = 0.60, p = 0.0003) and 12 (ρ = 0.44, p = 0.009) months, low contrast letter acuity at 6 (ρ = 0.35, p = 0.047) months, and RNFL thinning at 12 (ρ = 0.35, p = 0.044) months. Stratification of individual patient MTR time courses based on flux over 12 months (stable, putative remyelination and putative degeneration) predicted RNFL thinning at 12 months (F(2,32) = 3.59, p = 0.02). In conclusion, these findings indicate that MTR flux after acute ON is predictive of axonal degeneration and visual disability outcomes.
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ItemComparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips(BMC, 2011-03-08)BACKGROUND: Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. RESULTS: In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. CONCLUSIONS: CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.
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ItemEndogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis(BIOMED CENTRAL LTD, 2013)BACKGROUND: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system. RESULTS: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury. CONCLUSIONS: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
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ItemNo Preview AvailableA small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination(WILEY-BLACKWELL, 2013-05)The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B-expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo-dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases.
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ItemNo Preview AvailableOligodendroglial Expression of TrkB Independently Regulates Myelination and Progenitor Cell Proliferation(SOC NEUROSCIENCE, 2013-03-13)The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in regulating CNS myelination. BDNF mutant mice exhibit a hypomyelinating phenotype, and BDNF exerts distinct effects upon oligodendroglial proliferation, differentiation, and myelination in vitro. To investigate the precise influence that BDNF exerts in regulating CNS myelination in vivo, we have generated conditional knock-out mice in which TrkB has been deleted specifically in oligodendrocytes. Deletion of TrkB disrupted normal oligodendrocyte myelination, resulting in a significant reduction in myelin protein expression and myelination of CNS white matter tracts during development. Importantly, conditional knock-out mice exhibited normal numbers of mature oligodendrocytes and normal numbers of myelinated axons; however, myelin thickness was significantly reduced during development. These data indicate that while TrkB expression in oligodendrocytes plays no role in the initial contact with axons, it exerts an important influence in subsequent stages to promote myelin ensheathment. The conditional knock-out mice also exhibited an increased density of oligodendrocyte progenitor cells (OPCs) in CNS white matter tracts. Concordant with these results, in vitro analyses using OPCs subjected to TrkB knockdown also revealed increased OPC proliferation. Our data suggested this effect was dependent upon TrkC and p75 expression. Thus, our data demonstrate that TrkB expression in oligodendroglia exerts a direct effect on oligodendrocytes to promote myelination and an indirect effect upon the OPC population, modifying their proliferative potential.
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ItemNo Preview AvailableExtracellular signal-regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro(WILEY-BLACKWELL, 2012-09)Multiple extracellular factors have been implicated in orchestrating myelination of the CNS; however, less is known about the intracellular signaling cascades that regulate this process. We have previously shown that brain-derived neurotrophic factor (BDNF) promotes oligodendrocyte myelination. Here, we screened for the activation of candidate signaling pathways in in vitro myelination assays and found that extracellular signal-regulated kinase (Erk) signaling positively correlated with basal levels of oligodendrocyte myelination as well as BDNF-induced myelination in vitro. By selectively manipulating Erk1/2 activation in oligodendrocytes in vitro, we found that constitutive activation of Erk1/2 significantly increased myelination, mimicking the promyelinating effect of BDNF, and also caused myelination to occur earlier. Conversely, selective inhibition of Erk1/2 in oligodendrocytes significantly reduced the basal level of myelination and blocked the promyelinating effect of BDNF. Analysis of myelinating spinal cord and corpus callosum white matter tracts revealed that the majority of mature oligodendrocytes are co-labeled with phospho-Erk1/2, whereas phospho-Erk1/2 was rarely observed in oligodendrocyte progenitor cells. Finally, the total level of phospho-Erk1/2 correlated with myelin formation during the early postnatal period. Collectively, these data identify that Erk1/2 signaling within oligodendrocytes exerts an important and direct effect to promote myelination.