Florey Department of Neuroscience and Mental Health - Research Publications

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    Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects
    Beecroft, SJ ; Ayala, M ; McGillivray, G ; Nanda, V ; Agolini, E ; Novelli, A ; Digilio, MC ; Dotta, A ; Carrozzo, R ; Clayton, J ; Gaffney, L ; McLean, CA ; Ng, J ; Laing, NG ; Matteson, P ; Millonig, J ; Ravenscroft, G (WILEY, 2021-04-01)
    This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype observed in our patients. In silico protein modeling showed probable impairment of ALDH1A2 for three of the four substitutions. In vitro studies show a reduction of RA. Few pathogenic variants in genes encoding components of the retinoic signaling pathway have been described to date, likely due to embryonic lethality. Thus, this study contributes significantly to knowledge of the role of this pathway in human diaphragm and cardiovascular development and disease. Some clinical features in our patients are also observed in Fryns syndrome (MIM# 229850), syndromic microphthalmia 9 (MIM# 601186), and DiGeorge syndrome (MIM# 188400). Patients with similar clinical features who are genetically undiagnosed should be tested for recessive ALDH1A2-deficient malformation syndrome.
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    Distal oesophageal giant fibrovascular polyp in a patient with laparoscopic adjustable gastric band
    Yang, TWW ; Packiyanathan, A ; Tagkalidis, P ; McLean, C ; Brown, W (WILEY, 2021-03-18)
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    Erratum to: Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2020.
    Stehmann, C ; Senesi, M ; Sarros, S ; McGlade, A ; Lewis, V ; Simpson, M ; Klug, G ; McLean, C ; Masters, CL ; Collins, SJ (Australian Government Department of Health, 2021-08-09)
    Erratum to Commun Dis Intell (2018) 2021;45 (https://doi.org/10.33321/cdi.2021.45.38).
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    Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis (Retraction of Vol 30, art no 400, 2008)
    Atkin, JD ; Farg, MA ; Walker, AK ; McLean, C ; Tomas, D ; Horne, MK (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-02-05)
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    Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2020 (vol 22, 45, 2021)
    Stehmann, C ; Senesi, M ; Sarros, S ; McGlade, A ; Lewis, V ; Simpson, M ; Klug, G ; McLean, C ; Masters, CL ; Collins, S (AUSTRALIAN GOVERNMENT, DEPT HEALTH & AGEING, 2021-08-09)
    ABSTRACT: Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2020. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2020, 510 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2020, just over half (44 cases) of the 85 suspect case notifications remain classified as 'incomplete'; 27 cases were excluded through either detailed clinical follow-up (9 cases) or neuropathological examination (18 cases); 18 cases were classified as 'definite' and eleven as 'probable' prion disease. For 2020, sixty percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia.
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    Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer's Disease
    Hubbard, EE ; Heil, LR ; Merrihew, GE ; Chhatwal, JP ; Farlow, MR ; McLean, CA ; Ghetti, B ; Newell, KL ; Frosch, MP ; Bateman, RJ ; Larson, EB ; Keene, CD ; Perrin, RJ ; Montine, TJ ; MacCoss, MJ ; Julian, RR (AMER CHEMICAL SOC, 2022-01-07)
    One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.
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    Dramatic clinical response in the treatment of small cell glioblastoma multiforme
    Zaman, FY ; McLean, C ; Ameratunga, M (WILEY, 2022-01-11)
    WHAT IS KNOWN AND OBJECTIVE: Small cell glioblastoma (scGBM) is a rare subtype of primary glioblastoma, which typically behave more aggressively compared with classical glioblastoma (GBMs). They are generally associated with poor responses to treatment, and optimal treatment is not known. CASE SUMMARY: We present the case of a 51-year-old woman with scGBM with O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation, demonstrating an unexpected dramatic clinical response to chemoradiotherapy. WHAT IS NEW AND CONCLUSION: This case highlights that treatment with temozolomide-based chemoradiotherapy is justified in patients with scGBM, despite their poor prognosis. MGMT methylation may be associated with clinical responses.
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    Control of hippocampal prothrombin kringle-2 (pKr-2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice
    Kim, S ; Moon, GJ ; Kim, HJ ; Kim, D-G ; Kim, J ; Nam, Y ; Sharma, C ; Leem, E ; Lee, S ; Kim, K-S ; Ha, CM ; McLean, C ; Jin, BK ; Shin, W-H ; Kim, DW ; Oh, Y-S ; Hong, C-W ; Kim, SR (WILEY, 2021-10-24)
    BACKGROUND AND PURPOSE: There is a scarcity of information regarding the role of prothrombin kringle-2 (pKr-2), which can be generated by active thrombin, in hippocampal neurodegeneration and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: To assess the role of pKr-2 in association with the neurotoxic symptoms of AD, we determined pKr-2 protein levels in post-mortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared with those of age-matched controls and wild-type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by changes to pKr-2 up-regulation. KEY RESULTS: Our results demonstrated that pKr-2 was up-regulated in the hippocampi of patients with AD and 5XFAD mice, but was not associated with amyloid-β aggregation in 5XFAD mice. The up-regulation of pKr-2 expression was inhibited by preservation of the blood-brain barrier (BBB) via addition of caffeine to their water supply or by treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the prevention of up-regulation of pKr-2 expression reduced neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline due to neurotoxic inflammatory responses in 5XFAD mice. CONCLUSION AND IMPLICATIONS: We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr-2, which functions as an important pathogenic factor in the adult brain via blood brain barrier (BBB) breakdown. Thus, pKr-2 represents a novel target for AD therapeutic strategies and those for related conditions.
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    A method for simultaneous detection of small and long RNA biotypes by ribodepleted RNA-Seq
    Potemkin, N ; Cawood, SMF ; Treece, J ; Guevremont, D ; Rand, CJ ; McLean, C ; Stanton, J-AL ; Williams, JM (NATURE PORTFOLIO, 2022-01-12)
    RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was extremely efficient, resulting in less than 1.5% rRNA content in the final library. We identified > 30,000 unique transcripts from all samples, including protein-coding genes and many species of non-coding RNA, in biologically-relevant proportions. Furthermore, the normalized sequencing read count for select genes significantly negatively correlated with Ct values from qRT-PCR analysis from the same samples. These results indicate that this protocol accurately and consistently identifies and quantifies a wide variety of transcripts simultaneously. The highly efficient rRNA depletion, coupled with minimized sample handling and without complicated and high-loss size selection protocols, makes this protocol useful to researchers wishing to investigate whole transcriptomes.
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    The long and the short of Huntington's disease: how the sphingolipid profile is shifted in the caudate of advanced clinical cases.
    Phillips, GR ; Saville, JT ; Hancock, SE ; Brown, SHJ ; Jenner, AM ; McLean, C ; Fuller, M ; Newell, KA ; Mitchell, TW (Oxford University Press (OUP), 2022)
    Huntington's disease is a devastating neurodegenerative disorder that onsets in late adulthood as progressive and terminal cognitive, psychiatric and motor deficits. The disease is genetic, triggered by a CAG repeat (polyQ) expansion mutation in the Huntingtin gene and resultant huntingtin protein. Although the mutant huntingtin protein is ubiquitously expressed, the striatum degenerates early and consistently in the disease. The polyQ mutation at the N-terminus of the huntingtin protein alters its natural interactions with neural phospholipids in vitro, suggesting that the specific lipid composition of brain regions could influence their vulnerability to interference by mutant huntingtin; however, this has not yet been demonstrated in vivo. Sphingolipids are critical cell signalling molecules, second messengers and membrane components. Despite evidence of sphingolipid disturbance in Huntington's mouse and cell models, there is limited knowledge of how these lipids are affected in human brain tissue. Using post-mortem brain tissue from five brain regions implicated in Huntington's disease (control n = 13, Huntington's n = 13), this study aimed to identify where and how sphingolipid species are affected in the brain of clinically advanced Huntington's cases. Sphingolipids were extracted from the tissue and analysed using targeted mass spectrometry analysis; proteins were analysed by western blot. The caudate, putamen and cerebellum had distinct sphingolipid changes in Huntington's brain whilst the white and grey frontal cortex were spared. The caudate of Huntington's patients had a shifted sphingolipid profile, favouring long (C13-C21) over very-long-chain (C22-C26) ceramides, sphingomyelins and lactosylceramides. Ceramide synthase 1, which synthesizes the long-chain sphingolipids, had a reduced expression in Huntington's caudate, correlating positively with a younger age at death and a longer CAG repeat length of the Huntington's patients. The expression of ceramide synthase 2, which synthesizes very-long-chain sphingolipids, was not different in Huntington's brain. However, there was evidence of possible post-translational modifications in the Huntington's patients only. Post-translational modifications to ceramide synthase 2 may be driving the distinctive sphingolipid profile shifts of the caudate in advanced Huntington's disease. This shift in the sphingolipid profile is also found in the most severely affected brain regions of several other neurodegenerative conditions and may be an important feature of region-specific cell dysfunction in neurodegenerative disease.