Florey Department of Neuroscience and Mental Health - Research Publications

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    p21-activated kinase 4 controls the aggregation of α-synuclein by reducing the monomeric and aggregated forms of α-synuclein: involvement of the E3 ubiquitin ligase NEDD4-1.
    Won, S-Y ; Park, J-J ; You, S-T ; Hyeun, J-A ; Kim, H-K ; Jin, BK ; McLean, C ; Shin, E-Y ; Kim, E-G (Springer Science and Business Media LLC, 2022-06-30)
    Aggregation of misfolded alpha-synuclein (α-synuclein) is a central player in the pathogenesis of neurodegenerative diseases. Therefore, the regulatory mechanism underlying α-synuclein aggregation has been intensively studied in Parkinson's disease (PD) but remains poorly understood. Here, we report p21-activated kinase 4 (PAK4) as a key regulator of α-synuclein aggregation. Immunohistochemical analysis of human PD brain tissues revealed an inverse correlation between PAK4 activity and α-synuclein aggregation. To investigate their causal relationship, we performed loss-of-function and gain-of-function studies using conditional PAK4 depletion in nigral dopaminergic neurons and the introduction of lentivirus expressing a constitutively active form of PAK4 (caPAK4; PAK4S445N/S474E), respectively. For therapeutic relevance in the latter setup, we injected lentivirus into the striatum following the development of motor impairment and analyzed the effects 6 weeks later. In the loss-of-function study, Cre-driven PAK4 depletion in dopaminergic neurons enhanced α-synuclein aggregation, intracytoplasmic Lewy body-like inclusions and Lewy-like neurites, and reduced dopamine levels in PAK4DAT-CreER mice compared to controls. Conversely, caPAK4 reduced α-synuclein aggregation, as assessed by a marked decrease in both proteinase K-resistant and Triton X100-insoluble forms of α-synuclein in the AAV-α-synuclein-induced PD model. Mechanistically, PAK4 specifically interacted with the NEDD4-1 E3 ligase, whose pharmacological inhibition and knockdown suppressed the PAK4-mediated downregulation of α-synuclein. Collectively, these results provide new insights into the pathogenesis of PD and suggest PAK4-based gene therapy as a potential disease-modifying therapy in PD.
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    Prediction of disability-free survival in healthy older people.
    Neumann, JT ; Thao, LTP ; Murray, AM ; Callander, E ; Carr, PR ; Nelson, MR ; Wolfe, R ; Woods, RL ; Reid, CM ; Shah, RC ; Newman, AB ; Williamson, JD ; Tonkin, AM ; McNeil, JJ ; ASPREE investigators, (Springer Science and Business Media LLC, 2022-06)
    Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6-77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people.Trial registration Clinicaltrials.gov (NCT01038583).
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    Spinal extradural arachnoid cyst: A rare cause of thoracic myelopathy.
    Savage, AJ ; Asaid, M ; McLean, C ; Chan, P (Elsevier BV, 2022-09)
    A spinal extradural arachnoid cyst (SEAC) is a rare condition which can lead to back pain, radiculopathy, and compressive myelopathy. It accounts for approximately 1% of spinal tumours. The exact aetiology of SEACs is not well understood; however, this study is supportive of a traumatic aetiology of this disease in addition to supporting a uni-directional valve as a mechanism of CSF accumulation. The purpose of this study is to review the presentation, work-up, treatment and postoperative course of a patient with SEAC. We present the case of a 40-year-old male with a history of trauma who developed a SEAC and was treated surgically at our unit. Although a rare disease, we highlight the importance of early diagnosis and surgical treatment as it is a surgically curable disease with a good postoperative prognosis.
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    Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis
    Sadler, GL ; Lewis, KN ; Narayana, VK ; De Souza, DP ; Mason, J ; McLean, C ; Gonsalvez, DG ; Turner, BJ ; Barton, SK (MDPI, 2022-06-01)
    Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.
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    Phospholipid Profiles Are Selectively Altered in the Putamen and White Frontal Cortex of Huntington's Disease.
    Phillips, GR ; Hancock, SE ; Jenner, AM ; McLean, C ; Newell, KA ; Mitchell, TW (MDPI AG, 2022-05-16)
    Huntington's disease (HD) is a genetic, neurodegenerative illness that onsets in late adulthood as a series of progressive and terminal cognitive, motor, and psychiatric deficits. The disease is caused by a polyQ mutation in the Huntingtin gene (HTT), producing a polyglutamine expansion in the Huntingtin protein (HTT). HTT interacts with phospholipids in vitro; however, its interactions are changed when the protein is mutated in HD. Emerging evidence suggests that the susceptibility of brain regions to pathological stimuli is influenced by lipid composition. This study aimed to identify where and how phospholipids are changed in human HD brain tissue. Phospholipids were extracted using a modified MTBE method from the post-mortem brain of 13 advanced-stage HD patients and 13 age- and sex-matched controls. Targeted precursor ion scanning mass spectrometry was used to detect phospholipid species. In the white cortex of HD patients, there was a significantly lower abundance of phosphatidylcholine (PC) and phosphatidylserine (PS), but no difference in phosphatidylethanolamine (PE). In HD putamen, ester-linked 22:6 was lower in all phospholipid classes promoting a decrease in the relative abundance of ester polyunsaturated fatty acids in PE. No differences in phospholipid composition were identified in the caudate, grey cortex or cerebellum. Ether-linked PE fatty acids appear protected in the HD brain, as no changes were identified. The nature of phospholipid alterations in the HD brain is dependent on the lipid (subclass, species, and bond type) and the location.
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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.