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Article ; Online: Human Brain Neuropharmacology: A Platform for Translational Neuroscience.

Dragunow, Mike

2020 Volume 41, Issue 11, Page(s) 777–792

Abstract: Central nervous system (CNS) drug development has been plagued by a failure to translate effective therapies from the lab to the clinic. There are many potential reasons for this, including poor understanding of brain pharmacokinetic (PK) and ... ...

Abstract	Central nervous system (CNS) drug development has been plagued by a failure to translate effective therapies from the lab to the clinic. There are many potential reasons for this, including poor understanding of brain pharmacokinetic (PK) and pharmacodynamic (PD) factors, preclinical study flaws, clinical trial design issues, the complexity and variability of human brain diseases, as well as species differences. To address some of these problems, we have developed a platform for CNS drug discovery comprising: drug screening of primary adult human brain cells; human brain tissue microarray analysis of drug targets; and high-content phenotypic screening methods. In this opinion, I summarise the theoretical basis and the practical development and use of this platform in CNS drug discovery.
MeSH term(s)	Animals ; Brain Diseases/drug therapy ; Brain Diseases/pathology ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Humans ; Neuropharmacology/methods ; Translational Medical Research
Language	English
Publishing date	2020-09-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2020.09.002
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Article ; Online: Meningeal and choroid plexus cells--novel drug targets for CNS disorders.

Dragunow, Mike

Brain research

2013 Volume 1501, Page(s) 32–55

Abstract: The meninges and choroid plexus perform many functions in the developing and adult human central nervous system (CNS) and are composed of a number of different cell types. In this article I focus on meningeal and choroid plexus cells as targets for the ... ...

Abstract	The meninges and choroid plexus perform many functions in the developing and adult human central nervous system (CNS) and are composed of a number of different cell types. In this article I focus on meningeal and choroid plexus cells as targets for the development of drugs to treat a range of traumatic, ischemic and chronic brain disorders. Meningeal cells are involved in cortical development (and their dysfunction may be involved in cortical dysplasia), fibrotic scar formation after traumatic brain injuries (TBI), brain inflammation following infections, and neurodegenerative disorders such as Multiple Sclerosis (MS) and Alzheimer's disease (AD) and other brain disorders. The choroid plexus regulates the composition of the cerebrospinal fluid (CSF) as well as brain entry of inflammatory cells under basal conditions and after injuries. The meninges and choroid plexus also link peripheral inflammation (occurring in the metabolic syndrome and after infections) to CNS inflammation which may contribute to the development and progression of a range of CNS neurological and psychiatric disorders. They respond to cytokines generated systemically and secrete cytokines and chemokines that have powerful effects on the brain. The meninges may also provide a stem cell niche in the adult brain which could be harnessed for brain repair. Targeting meningeal and choroid plexus cells with therapeutic agents may provide novel therapies for a range of human brain disorders.
MeSH term(s)	Central Nervous System Diseases/drug therapy ; Central Nervous System Diseases/metabolism ; Central Nervous System Diseases/physiopathology ; Choroid Plexus/drug effects ; Choroid Plexus/metabolism ; Choroid Plexus/physiopathology ; Cytokines/metabolism ; Humans ; Inflammation/drug therapy ; Inflammation/metabolism ; Inflammation/physiopathology ; Meninges/drug effects ; Meninges/metabolism ; Meninges/physiopathology
Chemical Substances	Cytokines
Language	English
Publishing date	2013-03-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2013.01.013
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Article ; Online: Platelet-derived growth factor signalling in neurovascular function and disease.

Li, Susan Ys / Johnson, Rebecca / Smyth, Leon Cd / Dragunow, Mike

The international journal of biochemistry & cell biology

2022 Volume 145, Page(s) 106187

Abstract: Platelet-derived growth factors are critical for cerebrovascular development and homeostasis. Abnormalities in this signalling pathway are implicated in neurological diseases, especially those where neurovascular dysfunction and neuroinflammation plays a ...

Abstract	Platelet-derived growth factors are critical for cerebrovascular development and homeostasis. Abnormalities in this signalling pathway are implicated in neurological diseases, especially those where neurovascular dysfunction and neuroinflammation plays a prominent role in disease pathologies, such as stroke and Alzheimer's disease; the angiogenic nature of this pathway also draws its significance in brain malignancies such as glioblastoma where tumour angiogenesis is profuse. In this review, we provide an updated overview of the actions of the platelet-derived growth factors on neurovascular function, their role in the regulation of perivascular cell types expressing the cognate receptors, neurological diseases associated with aberrance in signalling, and highlight the clinical relevance and therapeutic potentials of this pathway for central nervous system diseases.
MeSH term(s)	Alzheimer Disease/metabolism ; Central Nervous System Diseases ; Humans ; Pericytes/metabolism ; Platelet-Derived Growth Factor ; Signal Transduction
Chemical Substances	Platelet-Derived Growth Factor
Language	English
Publishing date	2022-02-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2022.106187
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Article ; Online: Quantification of tumorsphere migration with a physics-based machine learning method.

Vong, Chun Kiet / Wang, Alan / Dragunow, Mike / Park, Thomas I-H / Shim, Vickie

Cytometry. Part A : the journal of the International Society for Analytical Cytology

2023 Volume 103, Issue 6, Page(s) 518–527

Abstract: Current analysis techniques available for migration assays only provide quantitative measurements for overall migration. However, the potential of regional migration analyses can open further insight into migration patterns and more avenues of ... ...

Abstract	Current analysis techniques available for migration assays only provide quantitative measurements for overall migration. However, the potential of regional migration analyses can open further insight into migration patterns and more avenues of experimentation with the same assays. Previously, we developed an analysis pipeline utilizing the finite element (FE) method to show its potential in analyzing glioblastoma (GBM) tumorsphere migration, especially in characterizing regional changes in the migration pattern. This study aims to streamline and further automate the analysis system by integrating the machine-learning-based U-Net segmentation with the FE method. Our U-Net-based segmentation achieved a 98% accuracy in segmenting our tumorspheres. From the segmentations, FE models made up of 3D hexahedral elements were generated, and the migration patterns of the tumorspheres were analyzed under treatments B and C (under non-disclosure agreements). Our results show that our overall migration analysis correlated very strongly (R
MeSH term(s)	Humans ; Machine Learning ; Glioblastoma/pathology ; Algorithms
Language	English
Publishing date	2023-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2099868-5
ISSN	1552-4930 ; 0196-4763 ; 1552-4922
ISSN (online)	1552-4930
ISSN	0196-4763 ; 1552-4922
DOI	10.1002/cyto.a.24722
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Article: Platelet-derived growth factor signalling in neurovascular function and disease

Li, Susan YS / Johnson, Rebecca / Smyth, Leon CD / Dragunow, Mike

Elsevier Ltd international journal of biochemistry & cell biology. 2022 Apr., v. 145

2022

Abstract	Platelet-derived growth factors are critical for cerebrovascular development and homeostasis. Abnormalities in this signalling pathway are implicated in neurological diseases, especially those where neurovascular dysfunction and neuroinflammation plays a prominent role in disease pathologies, such as stroke and Alzheimer’s disease; the angiogenic nature of this pathway also draws its significance in brain malignancies such as glioblastoma where tumour angiogenesis is profuse. In this review, we provide an updated overview of the actions of the platelet-derived growth factors on neurovascular function, their role in the regulation of perivascular cell types expressing the cognate receptors, neurological diseases associated with aberrance in signalling, and highlight the clinical relevance and therapeutic potentials of this pathway for central nervous system diseases.
Keywords	angiogenesis ; brain ; glioblastoma ; homeostasis ; platelet-derived growth factor ; stroke ; therapeutics
Language	English
Dates of publication	2022-04
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2022.106187
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Article ; Online: Cell Type-Specific Nuclei Markers: The Need for Human Brain Research to Go Nuclear.

Wiseman, James A / Dragunow, Mike / I-H Park, Thomas

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

2021 Volume 29, Issue 1, Page(s) 41–61

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	Humans ; Cell Nucleus/metabolism ; Brain/metabolism ; Neurons/metabolism ; Gene Expression Profiling ; Transcriptome
Language	English
Publishing date	2021-08-29
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1233753-5
ISSN	1089-4098 ; 1073-8584
ISSN (online)	1089-4098
ISSN	1073-8584
DOI	10.1177/10738584211037351
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Article: Alzheimer's Disease and Histone Code Alterations.

Narayan, Pritika / Dragunow, Mike

Advances in experimental medicine and biology

2017 Volume 978, Page(s) 321–336

Abstract: Substantial progress has been made in identifying Alzheimer's disease (AD) risk-associated variants using genome-wide association studies (GWAS). The majority of these risk variants reside in noncoding regions of the genome making their functional ... ...

Abstract	Substantial progress has been made in identifying Alzheimer's disease (AD) risk-associated variants using genome-wide association studies (GWAS). The majority of these risk variants reside in noncoding regions of the genome making their functional evaluation difficult; however, they also infer the presence of unconventional regulatory regions that may reside at these locations. We know from these studies that rare familial cases of AD account for less than 5% of all AD cases and autosomal dominant mutations in APP, PSEN1 and PSEN2 account for less than 10% of the genetic basis of these familial cases [1]. The sporadic form of AD, while more complex, still has a substantial genetic component evidenced by observational studies where 30-48% of AD patients have a first degree relative who is also affected [2]. In addition, the strongest risk factor after age is the APOE E4 polymorphism, and more than 20 other risk variants have been identified to date, reviewed in two recent papers [3, 4]. Monozygotic twin studies have revealed a discordance for AD, implicating that a combination of epigenetic and genetic factors are likely involved in the development of AD [5].
MeSH term(s)	Acetylation ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Apolipoprotein E4/genetics ; Brain Chemistry ; Disease Models, Animal ; Epigenesis, Genetic/genetics ; Histone Code/genetics ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Humans ; Methylation ; Mice ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Phosphorylation ; Protein Processing, Post-Translational/genetics ; Risk Factors
Chemical Substances	Apolipoprotein E4 ; Histone Deacetylase Inhibitors ; Histones ; Nerve Tissue Proteins ; histone methyltransferase (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-53889-1_17
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Article ; Online: A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue.

Cao, Maize C / Ryan, Brigid / Wu, Jane / Curtis, Maurice A / Faull, Richard L M / Dragunow, Mike / Scotter, Emma L

Neurobiology of disease

2023 Volume 185, Page(s) 106245

Abstract: TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the ... ...

Abstract	TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and differential exon usage are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. In this brief report, we identified markers of TDP-43 loss of function by depleting TARDBP from post-mortem human brain pericytes, a manipulable in vitro primary human brain cell model, and identifying differential exon usage events with bulk RNA-sequencing analysis. We present these data in an interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db-v2/) together with seven other TDP-43-depletion datasets we meta-analysed previously, for user analysis of differential expression and splicing signatures. Differential exon usage events that were validated by qPCR were then compiled into a 'differential exon usage panel' with other well-established TDP-43 loss-of-function exon markers. This differential exon usage panel was investigated in ALS and control motor cortex tissue to verify whether, and to what extent, TDP-43 loss of function occurs in ALS. We find that profiles of TDP-43-regulated cryptic exons, changed exon usage and changed 3' UTR usage discriminate ALS brain tissue from controls, verifying that TDP-43 loss of function occurs in ALS. We propose that TDP-43-regulated splicing events that occur in brain tissue will have promise as predictors of disease.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; RNA ; RNA Splicing
Chemical Substances	DNA-Binding Proteins ; RNA (63231-63-0) ; TARDBP protein, human
Language	English
Publishing date	2023-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2023.106245
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Article: Meningeal and choroid plexus cells—Novel drug targets for CNS disorders

Dragunow, Mike

Brain research. 2013 Mar. 21, v. 1501

2013

Abstract	The meninges and choroid plexus perform many functions in the developing and adult human central nervous system (CNS) and are composed of a number of different cell types. In this article I focus on meningeal and choroid plexus cells as targets for the development of drugs to treat a range of traumatic, ischemic and chronic brain disorders. Meningeal cells are involved in cortical development (and their dysfunction may be involved in cortical dysplasia), fibrotic scar formation after traumatic brain injuries (TBI), brain inflammation following infections, and neurodegenerative disorders such as Multiple Sclerosis (MS) and Alzheimer's disease (AD) and other brain disorders. The choroid plexus regulates the composition of the cerebrospinal fluid (CSF) as well as brain entry of inflammatory cells under basal conditions and after injuries. The meninges and choroid plexus also link peripheral inflammation (occurring in the metabolic syndrome and after infections) to CNS inflammation which may contribute to the development and progression of a range of CNS neurological and psychiatric disorders. They respond to cytokines generated systemically and secrete cytokines and chemokines that have powerful effects on the brain. The meninges may also provide a stem cell niche in the adult brain which could be harnessed for brain repair. Targeting meningeal and choroid plexus cells with therapeutic agents may provide novel therapies for a range of human brain disorders.
Keywords	Alzheimer disease ; adults ; brain ; cerebrospinal fluid ; chemokines ; choroid plexus ; drugs ; encephalitis ; humans ; inflammation ; meninges ; metabolic syndrome ; neurodegenerative diseases ; sclerosis ; stem cells
Language	English
Dates of publication	2013-0321
Size	p. 32-55.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2013.01.013
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Article ; Online: High-content analysis in neuroscience.

Dragunow, Mike

Nature reviews. Neuroscience

2008 Volume 9, Issue 10, Page(s) 779–788

Abstract: High-content analysis (HCA) combines automated microscopy and automated image analysis to quantify complex cellular anatomy and biochemistry objectively, accurately and quickly. High-content assays that are applicable to neuroscience include those that ... ...

Abstract	High-content analysis (HCA) combines automated microscopy and automated image analysis to quantify complex cellular anatomy and biochemistry objectively, accurately and quickly. High-content assays that are applicable to neuroscience include those that can quantify various aspects of dendritic trees, protein aggregation, transcription factor translocation, neurotransmitter receptor internalization, neuron and synapse number, cell migration, proliferation and apoptosis. The data that are generated by HCA are rich and multiplexed. HCA thus provides a powerful high-throughput tool for neuroscientists.
MeSH term(s)	Automation/instrumentation ; Automation/methods ; Cell Shape/physiology ; Computational Biology/instrumentation ; Computational Biology/methods ; Computational Biology/trends ; Image Cytometry/instrumentation ; Image Cytometry/methods ; Image Cytometry/trends ; Microscopy/instrumentation ; Microscopy/methods ; Microscopy/trends ; Neurochemistry/instrumentation ; Neurochemistry/methods ; Neurochemistry/trends ; Neurons/cytology ; Neurosciences/instrumentation ; Neurosciences/methods ; Neurosciences/trends ; Software/trends
Language	English
Publishing date	2008-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2034150-7
ISSN	1471-0048 ; 1471-0048 ; 1471-003X
ISSN (online)	1471-0048
ISSN	1471-0048 ; 1471-003X
DOI	10.1038/nrn2492
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