Mike Dragunow

University of Auckland

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Richard L. M. Faull

University of Auckland

141

Maurice A. Curtis

University of Auckland

Edward Mee

University of Auckland

Thomas Park

University of Auckland

Emma L. Scotter

University of Auckland

Justin Rustenhoven

Washington University in St. Louis

Patrick Schweder

University of Auckland

Clinton Turner

University of Auckland

Leon Smyth

Washington University in St. Louis

Henry J. Waldvogel

University of Auckland

Cooperative Institutions

University of Auckland

223

Brain Research New Zealand

University of Otago

Auckland City Hospital

Karolinska Institutet

King's College London

University of Gothenburg

Maurice Wilkins Centre

Instituto de Biomedicina de Sevilla

Universidad de Sevilla

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Motor neuron disease mortality rates in New Zealand 1992–2013

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (2018)

Maize C. Cao Andrew Chancellor Alison Charleston Mike Dragunow Emma L. Scotter

Background: We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no studies have examined MND rates nationwide to corroborate this. Methods: Death certificate data coded G12.2 by International Classification of Diseases (ICD)-10 coding, or 335.2 by ICD-9 coding were obtained. These codes specify amyotrophic lateral sclerosis, progressive bulbar palsy, or other motor neuron diseases as the underlying cause of death. Mortality rates for MND deaths in New Zealand were age-standardized to the European Standard Population and compared with rates from international studies that also examined death certificate data and were age-standardized to the same standard population. Results and Conclusion: The age-standardized mortality from MND in New Zealand was 2.3 per 100,000 per year from 1992–2007 and 2.8 per 100,000 per year from 2008–2013. These rates were 3.3 and 4.0 per 100,000 per year, respectively, for the population 20 years and older. The increase in rate between these two time periods was likely due to changes in MND death coding from 2008. Contrary to a previous regional study of MND incidence, nationwide mortality rates did not increase steadily over this time period once aging was accounted for. However, New Zealand MND mortality rate was higher than comparable studies we examined internationally (mean 1.67 per 100,000 per year), suggesting that further analysis of MND burden in New Zealand is warranted.

Death certificate

10.1080/21678421.2018.1432660

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Citations (5)

Presence of c-fos-like immunoreactivity in the adult rat brain

European Journal of Pharmacology (1987)

Mike Dragunow Marc R. Peterson H.A. Robertson

Solitary tract

Dorsal motor nucleus

c-Fos

Solitary nucleus

10.1016/0014-2999(87)90767-9

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Citations (82)

Cell Type–Specific Nuclei Markers: The Need for Human Brain Research to Go Nuclear

The Neuroscientist (2021)

James A. Wiseman Mike Dragunow Thomas Park

Identifying and interrogating cell type–specific populations within the heterogeneous milieu of the human brain is paramount to resolving the processes of normal brain homeostasis and the pathogenesis of neurological disorders. While brain cell type–specific markers are well established, most are localized on cellular membranes or within the cytoplasm, with limited literature describing those found in the nucleus. Due to the complex cytoarchitecture of the human brain, immunohistochemical studies require well-defined cell-specific nuclear markers for more precise and efficient quantification of the cellular populations. Furthermore, efficient nuclear markers are required for cell type–specific purification and transcriptomic interrogation of archived human brain tissue through nuclei isolation–based RNA sequencing. To sate the growing demand for robust cell type–specific nuclear markers, we thought it prudent to comprehensively review the current literature to identify and consolidate a novel series of robust cell type–specific nuclear markers that can assist researchers across a range of neuroscientific disciplines. The following review article collates and discusses several key and prospective cell type–specific nuclei markers for each of the major human brain cell types; it then concludes by discussing the potential applications of cell type–specific nuclear workflows and the power of nuclear-based neuroscientific research.

10.1177/10738584211037351

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Citations (1)

Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus

Brain Research (1997)

G.A. MacGibbon P. Lawlor Ernest Sirimanne M. Walton Bronwen Connor

Bcl-2-associated X protein

10.1016/s0006-8993(96)01351-0

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Citations (144)

CREB and neurodegeneration

Frontiers in bioscience (2004)

Mike Dragunow

Programmed cell death (PCD) is major concept in neurobiology and transcription factors are pivotal in switching on the nerve cell death program. More recently, the transcriptional control of programmed cell life (PCL) is beginning to be understood. This work began in studies of the activation of the CREB transcription factor in stroke models where it was shown that CREB is phosphorylated (and presumably activated) in neurons that survive this insult. In this review I will describe this data and also discuss the up-stream and down-stream pathways in this CREB neuroprotective transcriptional cassette. Finally, I will discuss studies showing that this CREB survival pathway may be inactivated by neurotoxins and genes involved in neurodegenerative disorders.

10.2741/1197

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Citations (39)

M3 muscarinic receptors as targets for drug development in neurodegenerative disorders

Nature Reviews Drug Discovery (2008)

Mike Dragunow

Drug Development

10.1038/nrd2506-c1

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Citations (3)

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate

Cell Communication and Signaling (2024)

Elizabeth Cooper Caitlin R. M. Oyagawa Rebecca Johnson Peter J. Choi Jena Macapagal Foliaki

Abstract Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate.

Palbociclib

10.1186/s12964-023-01277-z

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Citations (1)

Correlation between the induction of an immediate early gene,zif/268, and long-term potentiation in the dentate gyrus

Brain Research (1992)

Carol L. Richardson Warren P. Tate S.E. Mason P. Lawlor Mike Dragunow

LTP induction

Immediate early gene

Angular gyrus

10.1016/0006-8993(92)90938-6

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Citations (168)

Generalized seizures induce c-fos protein(s) in mammalian neurons

Neuroscience Letters (1987)

Mike Dragunow H.A. Robertson

Pentylenetetrazol

Piriform cortex

10.1016/0304-3940(87)90121-2

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Citations (212)

P10.03 Immunological differences between patient-matched normal-derived and GBM-derived pericytes

Neuro-Oncology (2019)

J Macapagal Anna E. S. Brooks Patrick Schweder Edward Mee Richard L. M. Faull

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is the most aggressive, fatal, yet most common form of brain malignancy in adults. Despite advances in immune-based treatments for other modes of cancer, GBM remains a challenge due to its ability to dampen immune responses via mechanisms not yet fully understood. With a median survival time of only 15 months following diagnosis, there is a strong push to find new targets for therapy. The microenvironment comprises a mixture of malignant tumour cells, stroma, blood vessels and infiltrating inflammatory cells. Despite advances in understanding the contribution of these cells in establishing an anti-inflammatory microenvironment, the contribution of pericytes, an important neurovascular mural cell that forms the blood-brain barrier, has been inadequately studied. Therefore, we investigated the differences in immune profile between patient-matched non-neoplastic brain- and GBM-derived pericytes under basal and induced conditions. MATERIAL AND METHODS Primary patient-matched non-neoplastic brain and GBM tumour derived pericytes were isolated from specimens excised from consenting patients undergoing GBM surgical resection at Auckland City Hospital. Pericytes were treated with inflammatory cytokines including IL-1β, IFN-γ, TNFα and TGFβ for up to 24 hours. Inflammatory profile changes were probed for using fluorescent immunocytochemistry, qRT-PCR and spectral flow cytometry. Media was also collected for secretome analysis via cytometric bead array. RESULTS GBM pericytes show decreased expression of CX3CL1, both basally and following IL-1β treatment, via qRT-PCR and CBA. In contrast, increased gene expression and secretion of IL-6 and IL-8 by GBM pericytes were observed. GBM pericytes also basally express CD90 and anti-inflammatory molecule PD-L1 compared to their normal counterparts. In terms of activated pathways, basal SMAD2/3 activation is increased in GBM pericytes, while also showing greater activation following treatment with IL-1β, IFN-γ but not TNFα. C/EBPδ is activated and translocated following inflammatory stimulation; however, shows localised expression within the cytoplasm only observed in GBM pericytes. CONCLUSION This immunological screen of GBM pericytes highlights them as key players in the establishment of the tumour microenvironment. With data suggesting the activation of pathways such as the SMAD2/3 pathway in an unconventional manner, it suggests the potential for pericytes to manipulate pathways towards a more immunosuppressive outcome. Further immune characterisation of such cells is required to fully understand how they might contribute to the immunosuppressive nature of GBM.

Pericyte

10.1093/neuonc/noz126.143

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