Publications by authors named "Glenda M Halliday"

326 Publications

Glycoprotein Pathways Altered in Frontotemporal Dementia With Autoimmune Disease.

Front Immunol 2021 1;12:736260. Epub 2021 Sep 1.

School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.

Behavioral variant frontotemporal dementia (bvFTD) is a younger onset form of neurodegeneration initiated in the frontal and/or temporal lobes with a slow clinical onset but rapid progression. bvFTD is highly complex biologically with different pathological signatures and genetic variants that can exhibit a spectrum of overlapping clinical manifestations. Although the role of innate immunity has been extensively investigated in bvFTD, the involvement of adaptive immunity in bvFTD pathogenesis is poorly understood. We analyzed blood serum proteomics to identify proteins that are associated with autoimmune disease in bvFTD. Eleven proteins (increased: ATP5B, CALML5, COLEC11, FCGBP, PLEK, PLXND1; decreased: APOB, ATP8B1, FAM20C, LOXL3, TIMD4) were significantly altered in bvFTD with autoimmune disease compared to those without autoimmune disease. The majority of these proteins were enriched for glycoprotein-associated proteins and pathways, suggesting that the glycome is targeted in bvFTD with autoimmune disease.
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http://dx.doi.org/10.3389/fimmu.2021.736260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440893PMC
September 2021

Author Correction: Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology.

Sci Rep 2021 Aug 26;11(1):17494. Epub 2021 Aug 26.

Discipline of Pathology and Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Rm 6211 Level 6W, Sydney, NSW, 2006, Australia.

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http://dx.doi.org/10.1038/s41598-021-97076-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390635PMC
August 2021

Progression of Clinical Features in Lewy Body Dementia Can Be Detected Over 6 Months.

Neurology 2021 09 17;97(10):e1031-e1040. Epub 2021 Aug 17.

From the Department of Psychiatry (E.M., S.R.W., A.S., J.T.O.) and MRC Biostatistics Unit (S.R.W.), University of Cambridge, UK; Forefront Parkinson's Disease Research Clinic (E.M., G.M.H., S.J.G.L.) and Brain and Mind Centre (E.M., G.M.H., S.J.G.L.), Faculty of Medicine and Health, University of Sydney, Australia; Newcastle Translational and Clinical Research Institute (J.-P.T., A.T., I.G.M.), Campus for Ageing and Vitality, Newcastle University, Newcastle Upon Tyne; and Centre for Public Health (J.P.M.K.), Queen's University Belfast, UK.

Objective: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance.

Methods: One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI).

Results: Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE ( = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points ( = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points ( = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable ( = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD.

Discussion: Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.
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http://dx.doi.org/10.1212/WNL.0000000000012450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448556PMC
September 2021

Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity.

J Neuroinflammation 2021 Aug 16;18(1):177. Epub 2021 Aug 16.

DANDRITE, The Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus C, Denmark.

Background: Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.

Methods: To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.

Results: We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.

Conclusion: α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.
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http://dx.doi.org/10.1186/s12974-021-02225-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369722PMC
August 2021

Native Separation and Metallation Analysis of SOD1 Protein from the Human Central Nervous System: a Methodological Workflow.

Anal Chem 2021 08 4;93(32):11108-11115. Epub 2021 Aug 4.

Univ. Bordeaux, CNRS, CENBG, UMR-5797, F-33170 Gradignan, France.

Studies of the metal content of metalloproteins in tissues from the human central nervous system (CNS) can be compromised by preparative techniques which alter levels of, or interactions between, metals and the protein of interest within a complex mixture. We developed a methodological workflow combining size exclusion chromatography, native isoelectric focusing, and either proton or synchrotron X-ray fluorescence within electrophoresis gels to analyze the endogenous metal content of copper-zinc superoxide dismutase (SOD1) purified from minimal amounts (<20 mg) of post-mortem human brain and spinal cord tissue. Abnormal metallation and aggregation of SOD1 are suspected to play a role in amyotrophic lateral sclerosis and Parkinson's disease, but data describing SOD1 metal occupancy in human tissues have not previously been reported. Validating our novel approach, we demonstrated step-by-step metal preservation, preserved SOD1 activity, and substantial enrichment of SOD1 protein versus confounding metalloproteins. We analyzed tissues from nine healthy individuals and five CNS regions (occipital cortex, substantia nigra, locus coeruleus, dorsal spinal cord, and ventral spinal cord). We found that Cu and Zn were bound to SOD1 in a ratio of 1.12 ± 0.28, a ratio very close to the expected value of 1. Our methodological workflow can be applied to the study of endogenous native SOD1 in a pathological context and adapted to a range of metalloproteins from human tissues and other sources.
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http://dx.doi.org/10.1021/acs.analchem.1c01128DOI Listing
August 2021

Alpha-synuclein research: defining strategic moves in the battle against Parkinson's disease.

NPJ Parkinsons Dis 2021 Jul 26;7(1):65. Epub 2021 Jul 26.

German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

With the advent of the genetic era in Parkinson's disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein's varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.
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http://dx.doi.org/10.1038/s41531-021-00203-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313662PMC
July 2021

Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson's Disease.

Front Cell Dev Biol 2021 6;9:612476. Epub 2021 Jul 6.

Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.

Parkinson's disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The disease is characterized by the progressive loss of dopaminergic neurons and spread of Lewy pathology (α-synuclein aggregates) in the brain but the pathogenesis remains elusive. PD presents substantial clinical and genetic variability. Although its complex etiology and pathogenesis has hampered the breakthrough in targeting disease modification, recent genetic tools advanced our approaches. As such, mitochondrial dysfunction has been identified as a major pathogenic hub for both familial and sporadic PD. In this review, we summarize the effect of mutations in 11 genes (, and ) on mitochondrial function as well as their relevance in the formation of Lewy pathology. Overall, these genes play key roles in mitochondrial homeostatic control (biogenesis and mitophagy) and functions (e.g., energy production and oxidative stress), which may crosstalk with the autophagy pathway, induce proinflammatory immune responses, and increase oxidative stress that facilitate the aggregation of α-synuclein. Thus, rectifying mitochondrial dysregulation represents a promising therapeutic approach for neuroprotection in PD.
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http://dx.doi.org/10.3389/fcell.2021.612476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291125PMC
July 2021

Author Correction: Parkinson disease-associated cognitive impairment.

Nat Rev Dis Primers 2021 Jul 13;7(1):53. Epub 2021 Jul 13.

Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s41572-021-00292-zDOI Listing
July 2021

Parkinson disease-associated cognitive impairment.

Nat Rev Dis Primers 2021 07 1;7(1):47. Epub 2021 Jul 1.

Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.
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http://dx.doi.org/10.1038/s41572-021-00280-3DOI Listing
July 2021

Neural mechanisms of psychosis vulnerability and perceptual abnormalities in the ALS-FTD spectrum.

Ann Clin Transl Neurol 2021 08 22;8(8):1576-1591. Epub 2021 Jun 22.

Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.

Objective: The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS-FTD.

Methods: In a prospective case-controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS-Plus), ALS-FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel-based morphometry analyses determined atrophy patterns in patients experiencing psychosis-like experiences and other perceptual abnormalities.

Results: The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS-FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer-based reports (18%) and self-report measures of psychotic-like experiences (21%). In an ENTER regression model, social anxiety and ACE-III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis-like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus.

Interpretation: The model for psychosis proneness in ALS-FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.
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http://dx.doi.org/10.1002/acn3.51363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351398PMC
August 2021

Comparison of Different Platform Immunoassays for the Measurement of Plasma Alpha-Synuclein in Parkinson's Disease Patients.

J Parkinsons Dis 2021 ;11(4):1761-1772

School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.

Background: The identification of reliable biomarkers in Parkinson's disease (PD) would provide much needed diagnostic accuracy, a means of monitoring progression, objectively measuring treatment response, and potentially allowing patient stratification within clinical trials. Whilst the assessment of total alpha-synuclein in biofluids has been identified as a promising biomarker, conflicting trends in these levels across patient plasma samples relative to controls has limited its use. Different commercially available assay platforms that have been used to measure alpha-synuclein may contribute to different study outcomes.

Objective: To compare different platform immunoassays for the measurement of total alpha-synuclein using the same plasma samples from 49 PD patients and 47 controls.

Methods: Total plasma alpha-synuclein concentrations were assessed using the BioLegend, MesoScale Discovery, and Quanterix platform in plasma samples from PD patients and matched controls.

Results: A significant increase in total plasma alpha-synuclein was observed in PD patients using the Biolegend (10%), Mesoscale Discovery (13%) and Quanterix (39%) assays. The Mesoscale Discovery and Quanterix assays showed the strongest correlations (r = 0.78, p < 0.0001) with each other, whilst the Quanterix platform demonstrated the lowest variation and highest effect size. Inclusion of age, sex and hemoglobin levels as covariates in the analysis of total alpha-synuclein improved the ability of all three immunoassays to detect a significant difference between patients and controls.

Conclusion: All three immunoassays were sensitive enough to detect group level differences between PD patients and controls, with the largest effect size observed with the Quanterix assay. These results may help inform assay choices in ongoing clinical trials.
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http://dx.doi.org/10.3233/JPD-212694DOI Listing
January 2021

Protein phosphatase 2A holoenzymes regulate leucine-rich repeat kinase 2 phosphorylation and accumulation.

Neurobiol Dis 2021 09 16;157:105426. Epub 2021 Jun 16.

Université de Lille, Inserm, CHU Lille, UMR-S1172, LilNCog, Lille Neuroscience & Cognition, 59000 Lille, France; Inserm, UMR-S 1172, Team "Brain Biology and Chemistry", 59000 Lille, France; KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium. Electronic address:

LRRK2 is a highly phosphorylated multidomain protein and mutations in the gene encoding LRRK2 are a major genetic determinant of Parkinson's disease (PD). Dephosphorylation at LRRK2's S910/S935/S955/S973 phosphosite cluster is observed in several conditions including in sporadic PD brain, in several disease mutant forms of LRRK2 and after pharmacological LRRK2 kinase inhibition. However, the mechanism of LRRK2 dephosphorylation is poorly understood. We performed a phosphatome-wide reverse genetics screen to identify phosphatases involved in the dephosphorylation of the LRRK2 phosphosite S935. Candidate phosphatases selected from the primary screen were tested in mammalian cells, Xenopus oocytes and in vitro. Effects of PP2A on endogenous LRRK2 phosphorylation were examined via expression modulation with CRISPR/dCas9. Our screening revealed LRRK2 phosphorylation regulators linked to the PP1 and PP2A holoenzyme complexes as well as CDC25 phosphatases. We showed that dephosphorylation induced by different kinase inhibitor triggered relocalisation of phosphatases PP1 and PP2A in LRRK2 subcellular compartments in HEK-293 T cells. We also demonstrated that LRRK2 is an authentic substrate of PP2A both in vitro and in Xenopus oocytes. We singled out the PP2A holoenzyme PPP2CA:PPP2R2 as a powerful phosphoregulator of pS935-LRRK2. Furthermore, we demonstrated that this specific PP2A holoenzyme induces LRRK2 relocalization and triggers LRRK2 ubiquitination, suggesting its involvement in LRRK2 clearance. The identification of the PPP2CA:PPP2R2 complex regulating LRRK2 S910/S935/S955/S973 phosphorylation paves the way for studies refining PD therapeutic strategies that impact LRRK2 phosphorylation.
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http://dx.doi.org/10.1016/j.nbd.2021.105426DOI Listing
September 2021

Prodromal neuroinvasion of pathological α-synuclein in brainstem reticular nuclei and white matter lesions in a model of α-synucleinopathy.

Brain Commun 2021 14;3(2):fcab104. Epub 2021 May 14.

Department of Biomedicine, Danish Research Institute of Translational Neuroscience (DANDRITE), Aarhus University, DK-8000 Aarhus C, Denmark.

Neuropathological observations in neurodegenerative synucleinopathies, including Parkinson disease, implicate a pathological role of α-synuclein accumulation in extranigral sites during the prodromal phase of the disease. In a transgenic mouse model of peripheral-to-central neuroinvasion and propagation of α-synuclein pathology (via hindlimb intramuscular inoculation with exogenous fibrillar α-synuclein: the M83 line, expressing the mutant human Ala53Thr α-synuclein), we studied the development and early-stage progression of α-synuclein pathology in the CNS of non-symptomatic (i.e. freely mobile) mice. By immunohistochemical analyses of phosphroylated α-synuclein on serine residue 129 (p-S129), our data indicate that the incipient stage of pathological α-synuclein propagation could be categorized in distinct phases: (i) initiation phase, whereby α-synuclein fibrillar inoculum induced pathological lesions in pools of premotor and motor neurons of the lumbar spinal cord, as early as 14 days post-inoculation; (ii) early central phase, whereby incipient α-synuclein pathology was predominantly detected in the reticular nuclei of the brainstem; and (iii) late central phase, characterized by additional sites of lesions in the brain including vestibular nuclei, deep cerebellar nuclei and primary motor cortex, with coincidental emergence of a sensorimotor deficit (mild degree of hindlimb clasping). Intriguingly, we also detected progressive α-synuclein pathology in premotor and motor neurons in the thoracic spinal cord, which does not directly innervate the hindlimb, as well as in the oligodendroglia within the white matter tracts of the CNS during this prodromal phase. Collectively, our data provide crucial insights into the spatiotemporal propagation of α-synuclein pathology in the nervous system of this rodent model of α-synucleinopathy following origin in periphery, and present a neuropathological context for the progression from pre-symptomatic stage to an early deficit in sensorimotor coordination. These findings also hint towards a therapeutic window for targeting the early stages of α-synuclein pathology progression in this model, and potentially facilitate the discovery of mechanisms relevant to α-synuclein proteinopathies. In a rodent model of synucleinopathy, Ferreira et al., delineate the spatiotemporal progression of incipient α-synuclein pathology (of peripheral origin) in the CNS. The authors show early affection of brainstem reticular nuclei in non-paralyzed mice, and pathological white matter lesions in relation to the neuronal pathology.
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http://dx.doi.org/10.1093/braincomms/fcab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202146PMC
May 2021

Reduced adult neurogenesis is associated with increased macrophages in the subependymal zone in schizophrenia.

Mol Psychiatry 2021 May 31. Epub 2021 May 31.

Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia.

Neural stem cells in the human subependymal zone (SEZ) generate neuronal progenitor cells that can differentiate and integrate as inhibitory interneurons into cortical and subcortical brain regions; yet the extent of adult neurogenesis remains unexplored in schizophrenia and bipolar disorder. We verified the existence of neurogenesis across the lifespan by chartering transcriptional alterations (2 days-103 years, n = 70) and identifying cells indicative of different stages of neurogenesis in the human SEZ. Expression of most neural stem and neuronal progenitor cell markers decreased during the first postnatal years and remained stable from childhood into ageing. We next discovered reduced neural stem and neuronal progenitor cell marker expression in the adult SEZ in schizophrenia and bipolar disorder compared to controls (n = 29-32 per group). RNA sequencing identified increased expression of the macrophage marker CD163 as the most significant molecular change in schizophrenia. CD163 macrophages, which were localised along blood vessels and in the parenchyma within 10 µm of neural stem and progenitor cells, had increased density in schizophrenia but not in bipolar disorder. Macrophage marker expression negatively correlated with neuronal progenitor marker expression in schizophrenia but not in controls or bipolar disorder. Reduced neurogenesis and increased macrophage marker expression were also associated with polygenic risk for schizophrenia. Our results support that the human SEZ retains the capacity to generate neuronal progenitor cells throughout life, although this capacity is limited in schizophrenia and bipolar disorder. The increase in macrophages in schizophrenia but not in bipolar disorder indicates that immune cells may impair neurogenesis in the adult SEZ in a disease-specific manner.
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http://dx.doi.org/10.1038/s41380-021-01149-3DOI Listing
May 2021

Glucocerebrosidase Activity is Reduced in Cryopreserved Parkinson's Disease Patient Monocytes and Inversely Correlates with Motor Severity.

J Parkinsons Dis 2021;11(3):1157-1165

Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney School of Medical Sciences, Camperdown, NSW, Australia.

Background: Reduced activity of lysosomal glucocerebrosidase is found in brain tissue from Parkinson's disease patients. Glucocerebrosidase is also highly expressed in peripheral blood monocytes where its activity is decreased in Parkinson's disease patients, even in the absence of GBA mutation.

Objective: To measure glucocerebrosidase activity in cryopreserved peripheral blood monocytes from 30 Parkinson's disease patients and 30 matched controls and identify any clinical correlation with disease severity.

Methods: Flow cytometry was used to measure lysosomal glucocerebrosidase activity in total, classical, intermediate, and non-classical monocytes. All participants underwent neurological examination and motor severity was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale.

Results: Glucocerebrosidase activity was significantly reduced in the total and classical monocyte populations from the Parkinson's disease patients compared to controls. GCase activity in classical monocytes was inversely correlated to motor symptom severity.

Conclusion: Significant differences in monocyte glucocerebrosidase activity can be detected in Parkinson's disease patients using cryopreserved mononuclear cells and monocyte GCase activity correlated with motor features of disease. Being able to use cryopreserved cells will facilitate the larger multi-site trials needed to validate monocyte GCase activity as a Parkinson's disease biomarker.
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http://dx.doi.org/10.3233/JPD-202508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461681PMC
January 2021

Comparison of Locus Coeruleus Pathology with Nigral and Forebrain Pathology in Parkinson's Disease.

Mov Disord 2021 09 26;36(9):2085-2093. Epub 2021 Apr 26.

ForeFront Research Team, Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia.

Background: Pathology in the noradrenergic A6 locus coeruleus has not been compared with more rostral dopaminergic A9 substantia nigra and A10 ventral tegmental area, and cholinergic Ch4 basal nucleus and Ch1/2 septal regions in the same cases of Parkinson's disease (PD).

Objective: To determine whether there is a gradient of caudal to rostral cell loss in PD.

Methods: Postmortem brains were collected from longitudinally followed donors with PD (n = 14) and aged-matched healthy donors (n = 13), six with restricted brainstem Lewy pathology (RLP), fixed in formalin and serial tissue slabs processed for cell and pathological quantitation. Noradrenergic A6 neurons were assessed and compared with previously published midbrain and basal forebrain data. From these data, regression estimates of pathological onset and progression were determined.

Results: Restricted Lewy pathology (RLP) cases had high pathological variability but no significant reduction in neurons. Pathology containing A6 neuron loss started at PD diagnosis and progressed faster (2.4% p.a) than the loss of dopaminergic A9 neurons (2% loss p.a.). Cases with dementia had significantly more pathology in noradrenergic and cholinergic neurons, had greater noradrenergic A6 neuron loss (29% more, progressing at 3.2% p.a.), and a selective loss of lateral A10 nonmelanized dopamine-producing neurons (starting a decade following diagnosis).

Conclusions: These findings show that in the same Parkinson's disease cases cell loss in these neurotransmitter systems does not follow a strict caudal to rostral trajectory and suggests symptom onset may relate to substantial pathology in the noradrenergic A6 locus coeruleus neurons in people with reduced dopamine-producing A9 substantia nigra neurons. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28615DOI Listing
September 2021

Coexisting Lewy body disease and clinical parkinsonism in amyotrophic lateral sclerosis.

Eur J Neurol 2021 07 16;28(7):2192-2199. Epub 2021 Apr 16.

Faculty of Medicine, Health and Human Sciences, School of Biomedical Sciences, Dementia Research Centre, Macquarie University, Sydney, NSW, Australia.

Background: Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) inclusions in motor and non-motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity.

Methods: All ALS cases held by the New South Wales Brain Bank (n = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined.

Results: Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities.

Conclusion: The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.
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http://dx.doi.org/10.1111/ene.14849DOI Listing
July 2021

Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis.

Neuropathol Appl Neurobiol 2021 Mar 23. Epub 2021 Mar 23.

Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease.

Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression.

Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix.

Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
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http://dx.doi.org/10.1111/nan.12709DOI Listing
March 2021

Globular glial tauopathy with a mutation in MAPT and unusual TDP-43 proteinopathy in a patient with behavioural-variant frontotemporal dementia.

Acta Neuropathol 2021 05 20;141(5):791-794. Epub 2021 Mar 20.

Dementia Research Centre, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.

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http://dx.doi.org/10.1007/s00401-021-02297-0DOI Listing
May 2021

Flow Cytometry Measurement of Glucocerebrosidase Activity in Human Monocytes.

Bio Protoc 2020 Apr 5;10(7):e3572. Epub 2020 Apr 5.

Brain and Mind Centre, University of Sydney, Sydney, Australia.

Glucocerebrosidase (GCase) is an important enzyme for the metabolism of glycolipids. GCase enzyme deficiency is implicated in human disease and the efficient measurement of GCase activity is important for evaluating the efficacy of therapeutics targeting this enzyme. Existing approaches to measure GCase activity include whole blood mass spectrometry-based assays, where an internal standard is used to measure the accumulation of ceramide following metabolism of the synthetic substrate C12-glucocerebroside, and the utilisation of fluorescent probes that bind active GCase and/or release fluorescent metabolites upon cleavage by GCase. Here, we describe the application of a fluorescence-activated cell sorter-based assay to efficiently quantitate GCase enzyme activity in the monocyte population of human peripheral blood mononuclear cells. The cell-permeable GCase substrate 5-(Pentafluorobenzoylamino) Fluorescein Di-beta-D-Glucopyranoside (PFB-FDGlu) provides a means to measure GCase activity, whereby enzymatic cleavage yields the green-fluorescent PFB-F dye, detectable in the FL-1 channel of a flow cytometer. An inhibitor of lysosomal GCase activity, conduritol B-epoxide, is employed to ensure specificity. This protocol provides an advantageous approach for measuring GCase activity in living individual cells.
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http://dx.doi.org/10.21769/BioProtoc.3572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842359PMC
April 2020

Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology.

Sci Rep 2021 Mar 1;11(1):4865. Epub 2021 Mar 1.

Discipline of Pathology and Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, Rm 6211 Level 6W, The University of Sydney, Sydney, NSW, 2006, Australia.

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The 'early' AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.
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http://dx.doi.org/10.1038/s41598-021-83872-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921390PMC
March 2021

Clinical and Biological Correlates of White Matter Hyperintensities in Patients With Behavioral-Variant Frontotemporal Dementia and Alzheimer Disease.

Neurology 2021 03 17;96(13):e1743-e1754. Epub 2021 Feb 17.

From the School of Psychology (K.H., O.P., R.L.-R.), Brain and Mind Centre (K.H., O.P., J.K., C.D.-S., G.M.H., J.R.H., R.L.-R.), Central Clinical School (J.K., C.D.-S., G.M.H., J.R.H.), The University of Sydney; and the School of Medical Sciences (J.K., C.D.-S., G.M.H., J.R.H.), University of New South Wales, Sydney, Australia.

Objective: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses.

Methods: A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed.

Results: Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD.

Conclusion: Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.
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http://dx.doi.org/10.1212/WNL.0000000000011638DOI Listing
March 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

J Neurol Neurosurg Psychiatry 2020 11 11. Epub 2020 Nov 11.

Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding () and unrelated genes (eg, ). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
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http://dx.doi.org/10.1136/jnnp-2020-322983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803890PMC
November 2020

A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes.

J Neuropathol Exp Neurol 2020 10;79(10):1122-1126

Discipline of Pathology, School of Medical Sciences.

This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.
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http://dx.doi.org/10.1093/jnen/nlaa100DOI Listing
October 2020

The complex relationship between genotype, pathology and phenotype in familial dementia.

Neurobiol Dis 2020 11 12;145:105082. Epub 2020 Sep 12.

The Brain and Mind Centre & School of Medical Sciences, Faculty of Medicine and Health, the University of Sydney, Sydney, Australia. Electronic address:

Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.
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http://dx.doi.org/10.1016/j.nbd.2020.105082DOI Listing
November 2020

Circular RNAs: The Brain Transcriptome Comes Full Circle.

Trends Neurosci 2020 10 20;43(10):752-766. Epub 2020 Aug 20.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia. Electronic address:

Circular RNAs (circRNAs) are a class of RNA molecules with a covalently closed loop structure formed by back-splicing of exon-exon junctions. The detection of circRNAs across many eukaryotic species, often with cell-type- and tissue-type-specific expression, has catalyzed a growing interest in understanding circRNA biogenesis and their potential functions. circRNAs are enriched in the brain, and accumulate upon neuronal differentiation and depolarization, suggesting that these RNAs are an integral component of the brain transcriptome, and may play functional roles. Here, we give an overview of the current understanding of circRNA biogenesis and function, discuss how circRNAs contribute to transcriptome complexity in the brain, and discuss recent data on the functional roles of circRNAs in the brain. We also discuss emerging data on the role of circRNAs in brain disorders and address common challenges of circRNA quantification in postmortem human brain.
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http://dx.doi.org/10.1016/j.tins.2020.07.007DOI Listing
October 2020

Antihypertensive medications ameliorate Alzheimer's disease pathology by slowing its propagation.

Alzheimers Dement (N Y) 2020 13;6(1):e12060. Epub 2020 Aug 13.

Neuroscience Research Australia (NeuRA) Sydney Australia.

Introduction: Mounting evidence supports an association between antihypertensive medication use and reduced risk of Alzheimer's disease (AD). Consensus on possible pathological mechanisms remains elusive.

Methods: Human brain tissue from a cohort followed to autopsy that included 96 cases of AD (46 medicated for hypertension) and 53 pathological controls (33 also medicated) matched for cerebrovascular disease was available from the New South Wales Brain Banks. Quantified frontal cortex amyloid beta (Aβ) and tau proteins plus Alzheimer's neuropathologic change scores were analyzed.

Results: Univariate analyses found no difference in amounts of AD proteins in the frontal cortex between medication users, but multivariate analyses showed that antihypertensive medication use was associated with a less extensive spread of AD proteins throughout the brain.

Discussion: The heterogeneous nature of the antihypertensive medications is consistent with downstream beneficial effects of blood pressure lowering and/or management being associated with the reduced spreading of AD pathology observed.
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http://dx.doi.org/10.1002/trc2.12060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424255PMC
August 2020

LRRK2 kinase inhibitors reduce alpha-synuclein in human neuronal cell lines with the G2019S mutation.

Neurobiol Dis 2020 10 13;144:105049. Epub 2020 Aug 13.

Neuroscience Research Australia, Sydney NSW 2031 & School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, NSW 2052, Australia; Brain and Mind Centre & Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia. Electronic address:

Kinase activating missense mutations in leucine-rich repeat kinase 2 (LRRK2) predispose to Parkinson's disease. Consequently, there is much interest in delineating LRRK2 biology, both in terms of gaining further insight into disease causes, and also determining whether or not LRRK2 is a potential Parkinson's disease therapeutic target. Indeed, many potent and selective small molecule inhibitors of LRRK2 have been developed and are currently being used for pre-clinical testing in cell and animal models. In the current study, we have obtained fibroblasts from four subjects with the common LRRK2 mutation, G2019S. Fibroblasts were reprogrammed to induced pluripotent stem cells and then to neural stem cells and ultimately neurons. Two clones for each of the human neural cell lines were then chronically treated with and without either of two distinct inhibitors of LRRK2 and effects on toxicity and Parkinson's disease related phenotypes were assessed. Cells with the G2019S mutation had a propensity to accumulate the pathological Parkinson's disease protein α-synuclein. Moreover, α-synuclein accumulation in the G2019S cells was significantly reduced with both LRRK2 inhibitors in seven of the eight cell lines studied. LRRK2 inhibitors also improved the nuclear morphology of G2019S cells and impacted on measures of autophagy and endoplasmic reticulum stress. Lastly, we did not find evidence of inhibitor toxicity under the chronic treatment conditions. These results add to evidence that LRRK2 inhibitors may have utility in the treatment of Parkinson's disease via reducing α-synuclein.
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http://dx.doi.org/10.1016/j.nbd.2020.105049DOI Listing
October 2020

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation.

Sci Rep 2020 08 13;10(1):13741. Epub 2020 Aug 13.

Brain and Mind Centre, The University of Sydney, Camperdown, Sydney, NSW, 2050, Australia.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that are considered to be on the same disease spectrum because of overlapping genetic, pathological and clinical traits. Changes in serum proteins in FTD and ALS are poorly understood, and currently no definitive biomarkers exist for diagnosing or monitoring disease progression for either disease. Here we applied quantitative discovery proteomics to analyze protein changes in FTD (N = 72) and ALS (N = 28) patient serum compared to controls (N = 22). Twenty three proteins were significantly altered in FTD compared to controls (increased-APOL1, C3, CTSH, EIF5A, MYH2, S100A8, SUSD5, WDR1; decreased-C1S, C7, CILP2, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, IGHV1, ITIH2, PROS1, SHBG, UMOD, VASN) and 14 proteins were significantly altered in ALS compared to controls (increased-APOL1, CKM, CTSH, IGHG1, IGKC, MYH2; decreased-C7, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, SHBG). There was substantial overlap in the proteins that were altered in FTD and ALS. These results were validated using western blotting. Gene ontology tools were used to assess functional pathways potentially dysregulated in the two diseases, and calcium ion binding and innate immunity pathways were altered in both diseases. When put together, these results suggest significant overlap in pathophysiological peripheral changes in FTD and ALS. This study represents the first proteomics side-by-side comparison of serum changes in FTD and ALS, providing new insights into under-recognized perturbed pathways and an avenue for biomarker development for FTD and ALS.
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http://dx.doi.org/10.1038/s41598-020-70687-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426269PMC
August 2020
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