Is the eye a window to the brain in Sanfilippo syndrome?

Published online: 17 November 2020Sanfilippo syndrome is an untreatable form of childhood-onset dementia. Whilst several therapeutic strategies are being evaluated in human clinical trials including i.v. delivery of AAV9-based gene therapy, an urgent unmet need is the availability of non-invasive, quantitative measures of neurodegeneration. We hypothesise that as part of the central nervous system, the retina may provide a window through which to 'visualise' degenerative lesions in brain and amelioration of them following treatment. This is reliant on the age of onset and the rate of disease progression being equivalent in retina and brain. For the first time we have assessed in parallel, the nature, age of onset and rate of retinal and brain degeneration in a mouse model of Sanfilippo syndrome. Significant accumulation of heparan sulphate and expansion of the endo/lysosomal system was observed in both retina and brain pre-symptomatically (by 3 weeks of age). Robust and early activation of micro- and macroglia was also observed in both tissues. There was substantial thinning of retina and loss of rod and cone photoreceptors by ~ 12 weeks of age, a time at which cognitive symptoms are noted. Intravenous delivery of a clinically relevant AAV9-human sulphamidase vector to neonatal mice prevented disease lesion appearance in retina and most areas of brain when assessed 6 weeks later. Collectively, the findings highlight the previously unrecognised early and significant involvement of retina in the Sanfilippo disease process, lesions that are preventable by neonatal treatment with AAV9-sulphamidase. Critically, our data demonstrate for the first time that the advancement of retinal disease parallels that occurring in brain in Sanfilippo syndrome, thus retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored.Helen Beard, Glyn Chidlow, Daniel Neumann, Nazzmer Nazri, Meghan Douglass, Paul J. Trim, Marten F. Snel, Robert J. Casson and Kim M. Hemsle

Tenth Scientific Biennial Meeting of the Australasian Virology Society-AVS10 2019

The Australasian Virology Society (AVS) aims to promote, support and advocate for the discipline of virology in the Australasian region. The society was incorporated in 2011 after 10 years operating as the Australian Virology Group (AVG) founded in 2001, coinciding with the inaugural biennial scientific meeting. AVS conferences aim to provide a forum for the dissemination of all aspects of virology, foster collaboration, and encourage participation by students and post-doctoral researchers. The tenth Australasian Virology Society (AVS10) scientific meeting was held on 2–5 December 2019 in Queenstown, New Zealand. This report highlights the latest research presented at the meeting, which included cutting-edge virology presented by our international plenary speakers Ana Fernandez-Sesma and Benjamin tenOever, and keynote Richard Kuhn. AVS10 honoured female pioneers in Australian virology, Lorena Brown and Barbara Coulson. We report outcomes from the AVS10 career development session on “Successfully transitioning from post-doc to lab head”, winners of best presentation awards, and the AVS gender equity policy, initiated in 2013. Plans for the 2021 meeting are underway which will celebrate the 20th anniversary of AVS where it all began, in Fraser Island, Queensland, Australia.Karla J. Helbig ... Michael R. Beard ... et al

Kimberlite metasomatism at Murowa and Sese pipes, Zimbabwe

The Cambrian-aged Murowa and Sese kimberlites are located within the Archean Zimbabwe Craton just N of the boundary with the Limpopo Mobile Zone. The root zones of pipes are exposed at the current erosion level. Kimberlite lithologies present are hypabyssal macrocrystic kimberlite (“HMK”), HMK breccia, tuffisitic kimberlite breccia (“TKB”) and minor lithic tuffisitic kimberlite breccia (“LTKB”). Country rocks are Archean 2.6 Ga Chibi and Zimbabwe granite batholiths. Kimberlite metasomatic effects are widespread, and can be laterally as extensive as the kimberlites themselves. The porphyritic granites are composed of fresh K- feldspar, oligoclase, quartz, biotite and muscovite. During initial metasomatism the granites become spotted with green chlorite, needles of alkaline amphiboles (winchite, riebeckite, arfvedsonite) and pyroxenes (aegirine-augite) with minor carbonate and felts of talc. Plagioclase becomes extensively altered, dusted and reddened with hematite, whereas K- feldspar remains unaffected. The granites become converted to syenite through removal of quartz. Similar fenitisation has been recorded at Toubabouko lamproite (Ivory Coast) (Knopf, 1970), Lesueur Township kimberlite in Quebec (Watson, 1973), Bow Hill ultramafic lamprophyre dyke (Jaques et al., 1986) and adjacent to the Lissadell Road lamproite dykes, Western Australia (C.B. Smith, unpublished data). As metasomatism intensifies at Murowa and Sese, veins of green metasomatite cut and disrupt the granite. Progressive disruption entrains granite blocks, breaking down the granite still further and transporting needle-like feldspar slivers, so giving rise to LTKB. The metasomatite chemistry is intermediate between granite and kimberlite, having lower Si, Al and Y than granite, similar amounts of K, Na, Ti and Ba, higher Ca, Mg, Ni, Cr, Nb, Sr, P, CO2, H2O+ and a higher Fe3+/Fe2+ ratio. Ferguson et al. (1973) described similar chemical alteration of wall rock adjacent to De Beers kimberlite pipe, South Africa The metasomatic process is analogous to the fenitisation of granitic wall rock by carbonatite. Kimberlite metasomatism at Murowa and Sese appears to be formed by fluids from the rising but pent-up proto-kimberlite melt penetrating into cracks and the matrix of the granite country rock and reacting with it. These fluids are alkaline, hydrous and CO2-rich, perhaps with affinities to the alkaline carbonates erupted from the Oldoinyo Lengai carbonatite volcano

Continual low-dose infusion of sulfamidase is superior to intermittent high-dose delivery in ameliorating neuropathology in the MPS IIIA mouse brain

Mucopolysaccharidosis IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder characterised by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of lysosomal sulfamidase results in accumulation of heparan sulfate and secondary storage of glycolipids in the brain. Intra-cisternal sulfamidase infusions reduce disease-related neuropathology; however, repeated injections may subject patients to the risk of infection and tissue damage so alternative approaches are required. We undertook a proof-of-principle study comparing the ability of slow/continual or repeat/bolus infusion to ameliorate neuropathology in MPS IIIA mouse brain. Six-week-old MPS IIIA mice were implanted with subcutaneously located mini-osmotic pumps filled with recombinant human sulfamidase (rhSGSH) or vehicle, connected to lateral ventricle-directed cannulae. Pumps were replaced at 8 weeks of age. Additional MPS IIIA mice received intra-cisternal bolus infusions of the same amount of rhSGSH (or vehicle), at 6 and 8 weeks of age. Unaffected mice received vehicle via each strategy. All mice were euthanised at 10 weeks of age and the brain was harvested to assess the effect of treatment on neuropathology. Mice receiving pump-delivered rhSGSH exhibited highly significant reductions in lysosomal storage markers (lysosomal integral membrane protein-2, GM3 ganglioside and filipin-positive lipids) and neuroinflammation (isolectin B4-positive microglia, glial fibrillary acidic protein-positive astroglia). MPS IIIA mice receiving rhSGSH via bolus infusion displayed reductions in these markers, but the effectiveness of the strategy was inferior to that seen with slow/pump-based delivery. Continual low-dose infusion may therefore be a more effective strategy for enzyme delivery in MPS IIIA.Helen Beard, Sofia Hassiotis, Amanda J. Luck, Tina Rozaklis, John J. Hopwood, Kim M. Hemsle

Axonal dystrophy in the brain of mice with Sanfilippo syndrome

Abstract not availableHelen Beard, Sofia Hassiotis, Wei-Ping Gai, Emma Parkinson-Lawrence, John J. Hopwood, Kim M. Hemsle

An integrated analysis of 33 Eucalyptus trials linking the onset of competition-induced tree growth suppression with management, physiographic and climatic factors

One of the greatest difficulties associated with controlling competitive vegetation during the establishment of eucalypts relates to the timing and planning of `weeding' operations. This may be due to site related variability in vegetation species distribution and abundance, climatic conditions and methods of site preparation. Using data from 33 eucalypt vegetation management trials, multivariate statistical techniques were used to determine whether any climatic, physiographic or management related variables could be related to the time taken for competition-induced tree growth suppression to occur. Altitude, the method of site preparation (burning versus not burning) and the interaction between these two factors were significantly related to the timing of tree growth suppression. Regardless of the method of site preparation, the onset of competition-induced tree growth suppression occurred earlier at lower altitudes, where the vegetation was more diverse and vigorous. At higher altitudes, burning appears to stimulate the earlier growth of vegetation, reducing the time for competition-induced tree growth suppression to occur.Une analyse intégrée de 33 essais avec des eucalyptus reliant le début de la baisse de croissance due à la compétition avec la gestion des peuplements, les facteurs physiographiques et climatiques. Une des grandes difficultés pour obtenir un contrôle de la végétation concurrentielle pendant l'installation de plantations d'eucalyptus est liée à la planification des opérations de désherbage. La difficulté provient de la variabilité de distribution et d'abondance des espèces qui constituent la végétation, des conditions climatiques et des méthodes de préparation du terrain. Des données de 33 essais de gestion de la végétation concurrente en plantation d'Eucalyptus ont été analysées avec des techniques statistiques multivariées pour identifier les variables climatiques, physiographiques ou de gestion susceptibles d'influencer l'apparition du ralentissement de croissance par la compétition herbacée. L'altitude, la méthode de préparation du terrain (brûlis ou non brûlis) et l'interaction entre ces deux facteurs ont eu un effet significatif sur ce ralentissement. Indépendamment de la méthode de préparation du terrain, le ralentissement de croissance se produisait plus précocement à basse altitude, là où la végétation était plus variée et plus vigoureuse. À plus haute altitude, le brûlis semble stimuler une croissance plus précoce de la végétation herbacée, en favorisant ainsi le ralentissement de la croissance des arbres

Viperin binds STING and enhances the type-I interferon response following dsDNA detection

First published: 01 November 2020Viperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin's broad antiviral activity by demonstrating the protein's ability to synergistically enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin's necessity to bind the cytosolic iron-sulphur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway; which results in an enhanced antiviral state. We also provide evidence for viperin's radical SAM enzymatic activity to self-limit its immunomodulatory functions. These data further define viperin's role as a positive regulator of innate immune signalling, offering a mechanism of viperin's broad antiviral capacity.Keaton M Crosse, Ebony A Monson, Arti B Dumbrepatil, Monique Smith, Yeu-Yang Tseng, Kylie H Van der Hoe

Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients' blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients' group with mitochondrial dysfunction "Psy-D", having high miR-137 and low COX6A2 levels in exosomes, and (b) a "Psy-ND" subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials