Florey Department of Neuroscience and Mental Health - Research Publications

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    Orphan peptide and G protein-coupled receptor signalling in alcohol use disorder
    Anversa, RG ; Maddern, XJ ; Lawrence, AJ ; Walker, LC (WILEY, 2024-03)
    Neuropeptides and G protein-coupled receptors (GPCRs) have long been, and continue to be, one of the most popular target classes for drug discovery in CNS disorders, including alcohol use disorder (AUD). Yet, orphaned neuropeptide systems and receptors (oGPCR), which have no known cognate receptor or ligand, remain understudied in drug discovery and development. Orphan neuropeptides and oGPCRs are abundantly expressed within the brain and represent an unprecedented opportunity to address brain function and may hold potential as novel treatments for disease. Here, we describe the current literature regarding orphaned neuropeptides and oGPCRs implicated in AUD. Specifically, in this review, we focus on the orphaned neuropeptide cocaine- and amphetamine-regulated transcript (CART), and several oGPCRs that have been directly implicated in AUD (GPR6, GPR26, GPR88, GPR139, GPR158) and discuss their potential and pitfalls as novel treatments, and progress in identifying their cognate receptors or ligands.
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    BRINGING THE BENCH TO THE BEDSIDE: UPDATES ON THE MIND STUDY AND WHAT A ROUTINELY AVAILABLE SIMPLE BLOOD TEST FOR NEUROFILAMENT LIGHT WOULD MEAN AT THE CLINICAL COAL FACE FOR PATIENTS AND FAMILIES, PSYCHIATRISTS, NEUROLOGISTS, GERIATRICIANS AND GENERAL PRACTITIONERS
    Eratne, D ; Lewis, C ; Cadwallader, C ; Kang, M ; Keem, M ; Santillo, A ; Li, QX ; Stehmann, C ; Loi, SM ; Walterfang, M ; Watson, R ; Yassi, N ; Blennow, K ; Zetterberg, H ; Janelidze, S ; Hansson, O ; Berry-Kravitz, E ; Brodtmann, A ; Darby, D ; Walker, A ; Dean, O ; Masters, CL ; Collins, S ; Berkovic, SF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2022-05)
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    Locus for severity implicates CNS resilience in progression of multiple sclerosis
    Harroud, A ; Stridh, PJ ; McCauley, JH ; Saarela, J ; van den Bosch, AMR ; Engelenburg, H ; Beecham, A ; Alfredsson, L ; Alikhani, K ; Amezcua, L ; Andlauer, TFM ; Ban, M ; Barcellos, L ; Barizzone, N ; Berge, T ; Berthele, A ; Bittner, S ; Bos, S ; Briggs, FBS ; Caillier, S ; Calabresi, P ; Caputo, D ; Carmona-Burgos, D ; Cavalla, P ; Celius, E ; Cerono, G ; Chinea, A ; Chitnis, T ; Clarelli, F ; Comabella, M ; Comi, G ; Cotsapas, C ; Cree, BCA ; D'Alfonso, S ; Dardiotis, E ; De Jager, P ; Delgado, S ; Dubois, B ; Engel, S ; Esposito, F ; Fabis-Pedrini, M ; Filippi, M ; Fitzgerald, K ; Gasperi, C ; Gomez, L ; Gomez, R ; Hadjigeorgiou, G ; Hamann, J ; Held, F ; Henry, R ; Hillert, J ; Huang, J ; Huitinga, I ; Islam, T ; Isobe, N ; Jagodic, M ; Kermode, AL ; Khalil, M ; Kilpatrick, T ; Konidari, I ; Kreft, K ; Lechner-Scott, J ; Leone, M ; Luessi, F ; Malhotra, S ; Manouchehrinia, A ; Manrique, C ; Martinelli-Boneschi, F ; Martinez, A ; Martinez-Maldonado, V ; Mascia, E ; Metz, L ; Midaglia, L ; Montalban, X ; Oksenberg, J ; Olsson, T ; Oturai, A ; Paakkonen, K ; Parnell, GP ; Patsopoulos, N ; Pericak-Vance, M ; Piehl, F ; Rubio, J ; Santaniello, A ; Santoro, S ; Schaefer, C ; Sellebjerg, F ; Shams, H ; Shchetynsky, K ; Silva, C ; Siokas, V ; Sondergaard, H ; Sorosina, M ; Taylor, B ; Vandebergh, M ; Vasileiou, E ; Vecchio, D ; Voortman, M ; Weiner, H ; Wever, D ; Yong, VW ; Hafler, D ; Stewart, G ; Compston, A ; Zipp, F ; Harbo, H ; Hemmer, B ; Goris, A ; Smolders, J ; Hauser, S ; Kockum, I ; Sawcer, S ; Baranzini, S ; Jonsdottir, I ; Blanco, Y ; Llufriu, S ; Madireddy, L ; Saiz, A ; Villoslada, P ; Stefansson, K ; Harbo, HF ; Hemmer, B ; Goris, A ; Kockum, I ; Sawcer, SJ ; Baranzini, SE (NATURE PORTFOLIO, 2023-07-13)
    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.
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    An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14
    Rafehi, H ; Read, J ; Szmulewicz, DJ ; Davies, KC ; Snell, P ; Fearnley, LG ; Scott, L ; Thomsen, M ; Gillies, G ; Pope, K ; Bennett, MF ; Munro, JE ; Ngo, KJ ; Chen, L ; Wallis, MJ ; Butler, EG ; Kumar, KR ; Wu, KHC ; Tomlinson, SE ; Tisch, S ; Malhotra, A ; Lee-Archer, M ; Dolzhenko, E ; Eberle, MA ; Roberts, LJ ; Fogel, BL ; Bruggemann, N ; Lohmann, K ; Delatycki, MB ; Bahlo, M ; Lockhart, PJ (CELL PRESS, 2023-01-05)
    Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.
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    The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
    Alexander, SPH ; Christopoulos, A ; Davenport, AP ; Kelly, E ; Mathie, AA ; Peters, JA ; Veale, EL ; Armstrong, JF ; Faccenda, E ; Harding, SD ; Davies, JA ; Abbracchio, MP ; Abraham, G ; Agoulnik, A ; Alexander, W ; Al-hosaini, K ; Baeck, M ; Baker, JG ; Barnes, NM ; Bathgate, R ; Beaulieu, J-M ; Beck-Sickinger, AG ; Behrens, M ; Bernstein, KE ; Bettler, B ; Birdsall, NJM ; Blaho, V ; Boulay, F ; Bousquet, C ; Braeuner-Osborne, H ; Burnstock, G ; Calo, G ; Castano, JP ; Catt, KJ ; Ceruti, S ; Chazot, P ; Chiang, N ; Chini, B ; Chun, J ; Cianciulli, A ; Civelli, O ; Clapp, LH ; Couture, R ; Cox, HM ; Csaba, Z ; Dahlgren, C ; Dent, G ; Douglas, SD ; Dournaud, P ; Eguchi, S ; Escher, E ; Filardo, EJ ; Fong, T ; Fumagalli, M ; Gainetdinov, RR ; Garelja, ML ; de Gasparo, M ; Gerard, C ; Gershengorn, M ; Gobeil, F ; Goodfriend, TL ; Goudet, C ; Graetz, L ; Gregory, KJ ; Gundlach, AL ; Hamann, J ; Hanson, J ; Hauger, RL ; Hay, DL ; Heinemann, A ; Herr, D ; Hollenberg, MD ; Holliday, ND ; Horiuchi, M ; Hoyer, D ; Hunyady, L ; Husain, A ; Ijzerman, AP ; Inagami, T ; Jacobson, KA ; Jensen, RT ; Jockers, R ; Jonnalagadda, D ; Karnik, S ; Kaupmann, K ; Kemp, J ; Kennedy, C ; Kihara, Y ; Kitazawa, T ; Kozielewicz, P ; Kreienkamp, H-J ; Kukkonen, JP ; Langenhan, T ; Larhammar, D ; Leach, K ; Lecca, D ; Lee, JD ; Leeman, SE ; Leprince, J ; Li, XX ; Lolait, SJ ; Lupp, A ; Macrae, R ; Maguire, J ; Malfacini, D ; Mazella, J ; Mcardle, CA ; Melmed, S ; Michel, MC ; Miller, LJ ; Mitolo, V ; Mouillac, B ; Mueller, CE ; Murphy, PM ; Nahon, J-L ; Ngo, T ; Norel, X ; Nyimanu, D ; O'Carroll, A-M ; Offermanns, S ; Panaro, MA ; Parmentier, M ; Pertwee, RG ; Pin, J-P ; Prossnitz, ER ; Quinn, M ; Ramachandran, R ; Ray, M ; Reinscheid, RK ; Rondard, P ; Rovati, GE ; Ruzza, C ; Sanger, GJ ; Schoeneberg, T ; Schulte, G ; Schulz, S ; Segaloff, DL ; Serhan, CN ; Singh, KD ; Smith, CM ; Stoddart, LA ; Sugimoto, Y ; Summers, R ; Tan, VP ; Thal, D ; Thomas, WW ; Timmermans, PBMWM ; Tirupula, K ; Toll, L ; Tulipano, G ; Unal, H ; Unger, T ; Valant, C ; Vanderheyden, P ; Vaudry, D ; Vaudry, H ; Vilardaga, J-P ; Walker, CS ; Wang, JM ; Ward, DT ; Wester, H-J ; Willars, GB ; Williams, TL ; Woodruff, TM ; Yao, C ; Ye, RD (WILEY, 2023-10)
    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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    Vitamin A metabolites inhibit ferroptosis
    Jakaria, M ; Belaidi, AA ; Bush, AI ; Ayton, S (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2023-08)
    Vitamin A (retinol) is a lipid-soluble vitamin that acts as a precursor for several bioactive compounds, such as retinaldehyde (retinal) and isomers of retinoic acid. Retinol and all-trans-retinoic acid (atRA) penetrate the blood-brain barrier and are reported to be neuroprotective in several animal models. We characterised the impact of retinol and its metabolites, all-trans-retinal (atRAL) and atRA, on ferroptosis-a programmed cell death caused by iron-dependent phospholipid peroxidation. Ferroptosis was induced by erastin, buthionine sulfoximine or RSL3 in neuronal and non-neuronal cell lines. We found that retinol, atRAL and atRA inhibited ferroptosis with a potency superior to α-tocopherol, the canonical anti-ferroptotic vitamin. In contrast, we found that antagonism of endogenous retinol with anhydroretinol sensitises ferroptosis induced in neuronal and non-neuronal cell lines. Retinol and its metabolites atRAL and atRA directly interdict lipid radicals in ferroptosis since these compounds displayed radical trapping properties in a cell-free assay. Vitamin A, therefore, complements other anti-ferroptotic vitamins, E and K; metabolites of vitamin A, or agents that alter their levels, may be potential therapeutics for diseases where ferroptosis is implicated.
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    Selective transduction and photoinhibition of pre-Bötzinger complex neurons that project to the facial nucleus in rats affects nasofacial activity
    Melo, MR ; Wykes, AD ; Connelly, AA ; Bassi, JK ; Cheung, SD ; Mcdougall, SJ ; Menuet, C ; Bathgate, RAD ; Allen, AM (eLIFE SCIENCES PUBL LTD, 2023-09-29)
    The pre-Bötzinger complex (preBötC), a key primary generator of the inspiratory breathing rhythm, contains neurons that project directly to facial nucleus (7n) motoneurons to coordinate orofacial and nasofacial activity. To further understand the identity of 7n-projecting preBötC neurons, we used a combination of optogenetic viral transgenic approaches to demonstrate that selective photoinhibition of these neurons affects mystacial pad activity, with minimal effects on breathing. These effects are altered by the type of anesthetic employed and also between anesthetized and conscious states. The population of 7n-projecting preBötC neurons we transduced consisted of both excitatory and inhibitory neurons that also send collaterals to multiple brainstem nuclei involved with the regulation of autonomic activity. We show that modulation of subgroups of preBötC neurons, based on their axonal projections, is a useful strategy to improve our understanding of the mechanisms that coordinate and integrate breathing with different motor and physiological behaviors. This is of fundamental importance, given that abnormal respiratory modulation of autonomic activity and orofacial behaviors have been associated with the development and progression of diseases.
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    Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice
    Pyun, J ; Koay, H ; Runwal, P ; Mawal, C ; Bush, AI ; Pan, Y ; Donnelly, PS ; Short, JL ; Nicolazzo, JA (MDPI, 2023-08)
    P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD.
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    Sustaining a New Model of Acute Stroke Care: A Mixed- Method Process Evaluation of the Melbourne Mobile Stroke Unit
    Bagot, KL ; Purvis, T ; Hancock, S ; Zhao, H ; Coote, S ; Easton, D ; Campbell, BC ; Davis, SM ; Donnan, GA ; Foster, S ; Langenberg, F ; Smith, K ; Stephenson, M ; Bernard, S ; McGowan, S ; Yan, B ; Mitchell, P ; Middleton, S ; Cadilhac, DA (KERMAN UNIV MEDICAL SCIENCES, 2023-01)
    BACKGROUND: Internationally, Mobile Stroke Unit (MSU) ambulances have changed pre-hospital acute stroke care delivery. MSU clinical and cost-effectiveness studies are emerging, but little is known about important factors for achieving sustainability of this innovative model of care. METHODS: Mixed-methods study from the Melbourne MSU (operational since November 2017) process evaluation. Participant purposive sampling included clinical, operational and executive/management representatives from Ambulance Victoria (AV) (emergency medical service provider), the MSU clinical team, and receiving hospitals. Sustainability was defined as ongoing MSU operations, including MSU workforce and future model considerations. Theoretically-based on-line survey with Unified Theory of Acceptance and Use of Technology (UTAUT), Self Determination Theory (SDT, Intrinsic Motivation), and open-text questions targeting barriers and benefits was administered (June-September 2019). Individual/group interviews were conducted, eliciting improvement suggestions and requirements for ongoing use. Descriptive and regression analyses (quantitative data) and directed content and thematic analysis (open text and interview data) were conducted. RESULTS: There were 135 surveys completed. Identifying that the MSU was beneficial to daily work (β=0.61), not experiencing pressure/tension about working on the MSU (β=0.17) and thinking they did well working within the team model (β=0.17) were significantly associated with wanting to continue working within the MSU model [R2=0.76; F(15, 60)=12.76, P<.001]. Experiences varied between those on the MSU team and those working with the MSU. Advantages were identified for patients (better, faster care) and clinicians (interdisciplinary learning). Disadvantages included challenges integrating into established systems, and establishing working relationships. Themes identified from 35 interviews were MSU team composition, MSU vehicle design and layout, personnel recruitment and rostering, communication improvements between organisations, telemedicine options, MSU operations and dispatch specificity. CONCLUSION: Important factors affecting the sustainability of the MSU model of stroke care emerged. A cohesive team approach, with identifiable benefits and good communication between participating organisations is important for clinical and operational sustainability.
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    The Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK.
    Li, V ; Binder, MD ; Kilpatrick, TJ (MDPI AG, 2023-11-02)
    Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone's tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone's effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.