Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Presynaptic neuronal antigens expressed by a small cell lung carcinoma cell line.

    24 October 2018

    Small cell lung carcinoma (SCLC) is a tumour of neuroendocrine origin often found in association with autoimmune paraneoplastic neurological disorders. We established a SCLC cell line from a woman with Lambert-Eaton myasthenic syndrome (LEMS) who developed antibodies to both the P/Q-type voltage-gated calcium channels (VGCC) and the muscle acetycholine receptor (AChR). We used a range of techniques to establish which neuronal antigens were expressed in her tumour cell line. The results show that many proteins involved in exocytosis are present in the SCLC cells, and that depolarisation-dependent release of [(3)H]-serotonin is linked to calcium influx through P/Q-type VGCCs. In addition, some of the subunits encoding the AChR and both agrin and ARIA, molecules released from the motor nerve during development, were expressed. These results suggest that many potential antigenic targets are present in SCLC, and indicate a surprising 'motor nerve terminal'-like characteristic of this line.

  • Antibodies to voltage-gated calcium channels in children with falciparum malaria.

    24 October 2018

    Falciparum malaria can affect the central nervous system (CNS), causing neurological dysfunction and sequelae. The pathophysiology of these complications is currently very poorly understood. Production of autoantibodies has frequently been reported as a consequence of infection with Plasmodium falciparum. However, at present, the presence of antibodies to components of the CNS during malaria infection has not been reported. We have sought to identify such antibodies, define their specificity, and determine whether they are involved in the development of neurological complications of falciparum malaria. Here, we show that, in a cohort of Kenyan children, levels of antibodies to the voltage-gated calcium channels, but not to other ion channels, increased with the severity of malaria infection.

  • Concurrent multiple sclerosis and amyotrophic lateral sclerosis: where inflammation and neurodegeneration meet?

    24 October 2018

    The concurrence of multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) is exceedingly rare and the pathological features have not been examined extensively. Here we describe the key pathological features of a 40 year old man with pathologically confirmed concurrent MS and ALS.This is the most pathologically illustrative case of coincident MS and ALS demonstrating inflammatory and neurodegenerative features characteristic of each disease, and is the first to exhibit the presence of TDP-43 inclusions in this clinical entity. The intricate relationship between neuroinflammation and neurodegeneration in these diseases is discussed.

  • The role of RNA processing in the pathogenesis of motor neuron degeneration.

    24 October 2018

    Motor neurons are large, highly polarised cells with very long axons and a requirement for precise spatial and temporal gene expression. Neurodegenerative disorders characterised by selective motor neuron vulnerability include various forms of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A rapid expansion in knowledge on the pathophysiology of motor neuron degeneration has occurred in recent years, largely through the identification of genes leading to familial forms of ALS and SMA. The major emerging theme is that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA. Complete understanding of how these pathways interact and elucidation of specialised mechanisms for mRNA targeting and processing in motor neurons are likely to produce new targets for therapy in ALS and related disorders.

  • The vascular basement membrane as "soil" in brain metastasis.

    24 October 2018

    Brain-specific homing and direct interactions with the neural substance are prominent hypotheses for brain metastasis formation and a modern manifestation of Paget's "seed and soil" concept. However, there is little direct evidence for this "neurotropic" growth in vivo. In contrast, many experimental studies have anecdotally noted the propensity of metastatic cells to grow along the exterior of pre-existing vessels of the CNS, a process termed vascular cooption. These observations suggest the "soil" for malignant cells in the CNS may well be vascular, rather than neuronal. We used in vivo experimental models of brain metastasis and analysis of human clinical specimens to test this hypothesis. Indeed, over 95% of early micrometastases examined demonstrated vascular cooption with little evidence for isolated neurotropic growth. This vessel interaction was adhesive in nature implicating the vascular basement membrane (VBM) as the active substrate for tumor cell growth in the brain. Accordingly, VBM promoted adhesion and invasion of malignant cells and was sufficient for tumor growth prior to any evidence of angiogenesis. Blockade or loss of the beta1 integrin subunit in tumor cells prevented adhesion to VBM and attenuated metastasis establishment and growth in vivo. Our data establishes a new understanding of CNS metastasis formation and identifies the neurovasculature as the critical partner for such growth. Further, we have elucidated the mechanism of vascular cooption for the first time. These findings may help inform the design of effective molecular therapies for patients with fatal CNS malignancies.

  • TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy.

    24 October 2018

    BACKGROUND: Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA). RESULTS: TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords. CONCLUSION: These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.

  • Collision lesions of the sella: co-existence of craniopharyngioma with gonadotroph adenoma and of Rathke's cleft cyst with corticotroph adenoma.

    24 October 2018

    Collision lesions of the sellar region are relatively uncommon. Most contributions include a pituitary adenoma or a cyst/cystic tumor, particularly a Rathke cleft cyst. The association of craniopharyngioma with an adenoma is particularly rare. Among reported cases, some have included secondary prolactin cell hyperplasia due to pituitary stalk section effect. Herein, we report two collision lesions, including a gonadotroph adenoma with adamantinomatous craniopharyngioma and a corticotroph adenoma with Rathke's cleft cyst. Clinicopathologic correlation and a review of the literature are undertaken.

  • Acromegaly and anaplastic astrocytoma: coincidence or pathophysiological relation?

    24 October 2018

    Insulin-like growth factor type I (IGF-I) is an important promoter in the tumorigenesis of several extracranial and intracranial neoplasms. In astrocytic-cell tumors, the role of autocrine and paracrine IGF-I expression in enhancing tumoral progression is well established. However, the influence of systemic IGF-I levels on the clinical behavior of astrocytic neoplasms remains an open subject of research. We report the case of a 28-year-old man who presented simultaneously with acromegaly and an anaplastic astrocytoma, which had rapidly progressed from a low-grade astrocytoma. The coexistence of systemic IGF-I hypersecretion with a quick progression in the histopathological grade of the astrocytoma raises the compelling question of whether the clinical behavior of the astrocytic tumor was influenced by the acromegalic status. The role of IGF-I signaling in the pathogenesis of astrocytic-cell tumors and the experience with therapeutic strategies addressing this pathway in astrocytomas are also discussed.