Cork NeuroScience Centre - Journal Articles

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    Editorial: the role of stem cells, epigenetics and micrornas in parkinson’s disease
    (Frontiers Media S.A., 2020) Hegarty, Shane V.; Green, Holly F.; Niclis, Jonathan; O'Keeffe, Gerard W.; Sullivan, Aideen M.
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    Association of distinct type 1 bone morphogenetic protein receptors with different molecular pathways and survival outcomes in neuroblastoma
    (Portland Press, 2020) Alshangiti, Amnah M.; Wyatt, Sean L.; McCarthy, Erin; Collins, Louise M.; Hegarty, Shane V.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Government of Saudi Arabia; Irish Research Council; Science Foundation Ireland
    Neuroblastoma (NB) is a paediatric cancer that arises in the sympathetic nervous system. Patients with stage 4 tumours have poor outcomes and 20% of high-risk cases have MYCN amplification. The bone morphogenetic proteins (BMPs) play roles in sympathetic neuritogenesis, by signalling through bone morphogenetic protein receptor (BMPR)2 and either BMPR1A or BMPR1B. Alterations in BMPR2 expression have been reported in NB; it is unknown if the expression of BMPR1A or BMPR1B is altered. We report lower BMPR2 and BMPR1B, and higher BMPR1A, expression in stage 4 and in MYCN-amplified NB. Kaplan–Meier plots showed that high BMPR2 or BMPR1B expression was linked to better survival, while high BMPR1A was linked to worse survival. Gene ontology enrichment and pathway analyses revealed that BMPR2 and BMPR1B co-expressed genes were enriched in those associated with NB differentiation. BMPR1A co-expressed genes were enriched in those associated with cell proliferation. Moreover, the correlation between BMPR2 and BMPR1A was strengthened, while the correlation between BMPR2 and BMPR1B was lost, in MYCN-amplified NB. This suggested that differentiation should decrease BMPR1A and increase BMPR1B expression. In agreement, nerve growth factor treatment of cultured sympathetic neurons decreased Bmpr1a expression and increased Bmpr1b expression. Overexpression of dominant negative BMPR1B, treatment with a BMPR1B inhibitor and treatment with GDF5, which signals via BMPR1B, showed that BMPR1B signalling is required for optimal neuritogenesis in NB cells, suggesting that loss of BMPR1B may alter neuritogenesis. The present study shows that expression of distinct BMPRs is associated with different survival outcomes in NB.
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    Growth differentiation factor 5 exerts neuroprotection in an a-synuclein rat model of Parkinson's disease
    (Oxford University Press, 2020-11-30) Goulding, Susan R.; Concannon, Ruth M.; Morales-Prieto, Noelia; Villalobos-Manriquez, Francisca; Clarke, Gerard; Collins, Louise M.; Lévesque, Martin; Wyatt, Sean L.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Science Foundation Ireland; Cork Institute of Technology
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    Preeclampsia and neurodevelopmental outcomes: Potential pathogenic roles for inflammation and oxidative stress?
    (Springer Nature Switzerland AG, 2021-01-25) Barron, Aaron; McCarthy, Cathal; O'Keeffe, Gerard W.; Irish Research Council; Health Research Board; Science Foundation Ireland
    Preeclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3–5% of first-time pregnancies and is a well-known leading cause of maternal and neonatal mortality and morbidity. In recent years, there has been accumulating evidence that in utero exposure to PE acts as an environmental risk factor for various neurodevelopmental disorders, particularly autism spectrum disorder and ADHD. At present, the mechanism(s) mediating this relationship are uncertain. In this review, we outline the most recent evidence implicating a causal role for PE exposure in the aetiology of various neurodevelopmental disorders and provide a novel interpretation of neuroanatomical alterations in PE-exposed offspring and how these relate to their sub-optimal neurodevelopmental trajectory. We then postulate that inflammation and oxidative stress, two prominent features of the pathophysiology of PE, are likely to play a major role in mediating this association. The increased inflammation in the maternal circulation, placenta and fetal circulation in PE expose the offspring to both prenatal maternal immune activation—a risk factor for neurodevelopmental disorders, which has been well-characterised in animal models—and directly higher concentrations of pro-inflammatory cytokines, which adversely affect neuronal development. Similarly, the exaggerated oxidative stress in the mother, placenta and foetus induces the placenta to secrete factors deleterious to neurons, and exposes the fetal brain to directly elevated oxidative stress and thus adversely affects neurodevelopmental processes. Finally, we describe the interplay between inflammation and oxidative stress in PE, and how both systems interact to potentially alter neurodevelopmental trajectory in exposed offspring.