Publications by authors named "George D Mellick"

105 Publications

Sycosterol A, an α-Synuclein Inhibitory Sterol from the Australian Ascidian .

J Nat Prod 2021 Nov 17. Epub 2021 Nov 17.

School of Environment and Science, Griffith University (Gold Coast Campus), Parklands Drive, Southport, QLD 4222, Australia.

During a recent biodiscovery study to identify new α-synuclein (α-syn) aggregation inhibitors, we screened 29 Australian marine sponge and ascidian extracts in an MS binding assay. This resulted in an extract from the ascidian showing activity toward α-syn. The bioassay and MS guided isolation process led to the identification of one new polyoxygenated sterol sulfate, sycosterol A (). The structure of this low-yielding steroid was elucidated from HRMS and NMR analysis. Sycosterol A displayed moderate antiaggregation activity with 46.2% (±1.8) inhibition when screened against α-syn at a 5:1 (sycosterol A:α-syn) molar ratio. The α-syn antiaggregation activity displayed by and the recent discovery of similar sterols with α-syn antiaggregation activity and potent antiprion activity suggest this unique class may be useful antineurodegenerative compounds.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00768DOI Listing
November 2021

Calcium channels and iron metabolism: A redox catastrophe in Parkinson's disease and an innovative path to novel therapies?

Redox Biol 2021 11 15;47:102136. Epub 2021 Sep 15.

Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia; School of Environment and Science, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia. Electronic address:

Autonomously spiking dopaminergic neurons of the substantia nigra pars compacta (SNpc) are exquisitely specialized and suffer toxic iron-loading in Parkinson's disease (PD). However, the molecular mechanism involved remains unclear and critical to decipher for designing new PD therapeutics. The long-lasting (L-type) Ca1.3 voltage-gated calcium channel is expressed at high levels amongst nigral neurons of the SNpc, and due to its role in calcium and iron influx, could play a role in the pathogenesis of PD. Neuronal iron uptake via this route could be unregulated under the pathological setting of PD and potentiate cellular stress due to its redox activity. This Commentary will focus on the role of the Ca1.3 channels in calcium and iron uptake in the context of pharmacological targeting. Prospectively, the audacious use of artificial intelligence to design innovative Ca1.3 channel inhibitors could lead to breakthrough pharmaceuticals that attenuate calcium and iron entry to ameliorate PD pathology.
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http://dx.doi.org/10.1016/j.redox.2021.102136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517601PMC
November 2021

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

J Parkinsons Dis 2021 Oct 7. Epub 2021 Oct 7.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation.

Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases.

Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017).

Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking.

Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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http://dx.doi.org/10.3233/JPD-212851DOI Listing
October 2021

Hunting for Familial Parkinson's Disease Mutations in the Post Genome Era.

Genes (Basel) 2021 03 17;12(3). Epub 2021 Mar 17.

Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, Australia.

Parkinson's disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The p.G2019S mutation causes PD in 42.5-68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.
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http://dx.doi.org/10.3390/genes12030430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002626PMC
March 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 03 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

The Queensland Parkinson's Project: An Overview of 20 Years of Mortality from Parkinson's Disease.

J Mov Disord 2021 Jan 7;14(1):34-41. Epub 2020 Dec 7.

Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, Australia.

Objective: The consensus is that life expectancy for individuals with Parkinson's disease (PD) is reduced, but estimations vary. We aimed to provide an overview of 20 years of mortality and risk factor data from the Queensland Parkinson's Project.

Methods: The analysis included 1,334 PD and 1,127 control participants. Preliminary analysis of baseline characteristics (sex, age at onset, family history, smoking status, pesticide exposure, depression and neurosurgery) was conducted, and Kaplan-Meier curves were generated for each potential risk factor. Standardized mortality ratios (SMRs) were calculated comparing this cohort to the general Australian population. Cox proportional hazards regression modeling was used to analyze potential predictors of mortality.

Results: In total, 625 (46.8%) PD and 237 (21.0%) control participants were deceased. Mean disease duration until death was 15.3 ± 7.84 years. Average ages at death were 78.0 ± 7.4 years and 80.4 ± 8.4 years for the deceased PD and control participants, respectively. Mortality was significantly increased for PD in general {SMR = 2.75 [95% confidence interval (CI): 2.53-2.96]; p = 0.001}. SMRs were slightly higher for women and those with an age of onset before 60 years. Multivariate analysis showed that deep brain stimulation (DBS) treatment was associated with lower mortality [hazard ratio (HR) = 0.76; 95% CI: 0.59-0.98], while occasional pesticide exposure increased mortality risk (HR = 1.48; 95% CI: 1.17-1.88). Family history of PD, smoking and depression were not independent predictors of mortality.

Conclusion: Mortality in PD is increased. Sex, age at onset and occasional pesticide exposure were independent determinants of increased mortality, while DBS treatment was associated with reduced mortality.
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http://dx.doi.org/10.14802/jmd.20034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840238PMC
January 2021

Anti-prion and α-Synuclein Aggregation Inhibitory Sterols from the Sponge cf. .

J Nat Prod 2020 12 3;83(12):3751-3757. Epub 2020 Dec 3.

Environmental Futures Research Institute, Griffith University (Gold Coast campus), Parklands Drive, Southport, QLD 4222, Australia.

In a study aimed at identifying new anti-prion compounds we screened a library of 500 Australian marine invertebrate derived extracts using a yeast-based anti-prion assay. This resulted in an extract from the subtropical sponge cf. showing potent anti-prion activity. The bioassay-guided investigation of the sponge extract led to the isolation of three new bioactive polyoxygenated steroids, lamellosterols A-C (-). These sterols were all isolated in low yield, and their structures elucidated by extensive NMR and MS data analysis. Lamellosterols A-C displayed potent anti-prion activity against the [] yeast prion (ECs of 12.7, 13.8, and 9.8 μM, respectively). Lamellosterol A () was further shown to bind to the Parkinson's disease implicated amyloid protein, α-synuclein, and to significantly inhibit its aggregation. Our findings indicate that these polyoxygenated sterol sulfates may be useful compounds to study mechanisms associated with neurodegenerative diseases.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01168DOI Listing
December 2020

Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons.

Mov Disord 2021 03 3;36(3):704-715. Epub 2020 Nov 3.

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson's disease (PD), clinically representing typical PD.

Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation.

Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons.

Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy.

Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048506PMC
March 2021

Chemical constituents from Macleaya cordata (Willd) R. Br. and their phenotypic functions against a Parkinson's disease patient-derived cell line.

Bioorg Med Chem 2020 11 28;28(21):115732. Epub 2020 Aug 28.

Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia. Electronic address:

Cytological profiling (CP) assay against a human olfactory neuroshpere-derived (hONS) cell line using a library of traditional Chinese medicinal plant extracts gave indications that the ethanolic extract of Macleaya cordata (Willd) R. Br. elicited strong perturbations to various cellular components. Further chemical investigation of this extract resulted in the isolation of two new benzo[c]phenanthridine alkaloids, (6R)-10-methoxybocconoline (1) and 6-(1-hydroxyethyl)-10-methoxy-5,6-dihydrochelerythrine (2). Their planar structures were elucidated by extensive 1D and 2D NMR studies, together with MS data. The absolute configuration for position C-6 of 1 and relative configurations for position C-6 and C-1' of 2 were assigned by density functional theory (DFT) calculations of ECD and NMR data, respectively. Also isolated were fourteen known metabolites, including ten alkaloids (3-12) and four coumaroyl-containing compounds (13-16). Cytological profiling of the isolates against Parkinson's Disease (PD) patient-derived olfactory cells revealed bocconoline (3) and 6-(1-hydroxyethyl)-5,6-dihydrochelerythrine (4) significantly perturbated the features of cellular organelles including early endosomes, mitochondria and autophagosomes. Given that hONS cells from PD patients model some functional aspects of the disease, the results suggested that these phenotypic profiles may have a role in the mechanisms underlying PD and signified the efficacy of CP in finding potential chemical tools to study the biological pathways in PD.
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http://dx.doi.org/10.1016/j.bmc.2020.115732DOI Listing
November 2020

Perspective: Current Pitfalls in the Search for Future Treatments and Prevention of Parkinson's Disease.

Front Neurol 2020 8;11:686. Epub 2020 Jul 8.

School of Environment and Science, Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.

We are gradually becoming aware that there is more to Parkinson's disease (PD) than meets the eye. Accumulating evidence has unveiled a disease complexity that has not (yet) been incorporated into ongoing efforts aimed at slowing, halting or reversing the course of PD, likely underlying their lack of success. There is a substantial latency between the actual onset of PD pathology and our ability to confirm diagnosis, during which accumulating structural and functional damage might be too advanced for effective modification or protection. Identification at the earliest stages of the disease course in the absence of Parkinsonism is crucial if we are to intervene when it matters most. Prognostic and therapeutic inferences can only be successful if we are able to accurately predict who is at risk for developing PD and if we can differentiate amongst the considerable clinicopathologic diversity. Biomarkers can greatly improve our identification and differentiation abilities if we are able to disentangle cause and effect.
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http://dx.doi.org/10.3389/fneur.2020.00686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360677PMC
July 2020

Genetic Analysis of in an Early-Onset Parkinson's Disease Cohort.

Front Neurol 2020 26;11:523. Epub 2020 Jun 26.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, VIC, Australia.

Pathogenic variants in the gene encoding RAB39B, resulting in the loss of protein function, lead to the development of X-linked early-onset parkinsonism. The gene is located within a chromosomal region that is susceptible to genomic rearrangement, and while an increased dosage of was previously associated with cognitive impairment, the potential role of dosage alterations in Parkinson's disease (PD) remains to be determined. This study aimed to investigate the contribution of the genetic variation in RAB39B to the development of early-onset PD. We performed gene dosage studies and sequence analysis in a cohort of 176 individuals with early-onset PD (age of onset ≤ 50 years) of unknown genetic etiology. An assessment of the copy number variation over both coding exons and the 3' untranslated region (UTR) of did not identify any alterations in gene dosage. An analysis of the UTRs identified two male individuals carrying single, likely benign, nucleotide variants in the 3'UTR (chrX:154489749-A-G and chrX:154489197-T-G). Furthermore, one novel variant of uncertain significance was identified in the 5'UTR, 229 bp upstream of the start codon (chrX:154493802-C-T). analyses predicted that this variant disrupts a highly conserved transcription factor binding site and could impact expression. The results of this study do not support a significant role for genetic variation in as contributing to early-onset PD but do highlight that additional molecular studies are required to determine the mechanisms regulating expression and their association with the disease. Genetic investigations in larger parkinsonism/PD cohorts and longitudinal studies of individuals with cognitive impairment due to an altered dosage of will be required to fully delineate the contribution of RAB39B to parkinsonism.
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http://dx.doi.org/10.3389/fneur.2020.00523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332711PMC
June 2020

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

Mov Disord 2020 10 14;35(10):1755-1764. Epub 2020 Jul 14.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.

Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.

Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.

Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (OR , 0.38; 95% CI, 0.21-0.67 and OR , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (OR , 0.19; 95% CI, 0.07-0.50 and OR , 0.51; 95% CI, 0.28-0.91).

Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572560PMC
October 2020

Novel Furan-2-yl-1-pyrazoles Possess Inhibitory Activity against α-Synuclein Aggregation.

ACS Chem Neurosci 2020 08 8;11(15):2303-2315. Epub 2020 Jul 8.

School of Pharmacy and Pharmacology, Griffith University, Gold Coast, Queensland 4222, Australia.

A series of novel furan-2-yl-1-pyrazoles and their chemical precursors were synthesized and evaluated for their effectiveness at disrupting α-synuclein (α-syn) aggregation . The compounds were found to inhibit α-syn aggregation with efficacy comparable to the promising drug candidate anle138b. The results of this study indicate that compounds , , and may qualify as secondary leads for the structure-activity relationship studies aimed to identify the suitable compounds for improving the modulatory activity targeted at α-syn self-assembly related to Parkinson's disease.
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http://dx.doi.org/10.1021/acschemneuro.0c00252DOI Listing
August 2020

Evidence of a Recessively Inherited CCN3 Mutation as a Rare Cause of Early-Onset Parkinsonism.

Front Neurol 2020 15;11:331. Epub 2020 May 15.

Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.

The study of consanguineous families has provided novel insights into genetic causes of monogenic parkinsonism. Here, we present a family from the rural Khyber Pakhtunkhwa province, Pakistan, where three siblings were diagnosed with early-onset parkinsonism. Homozygosity mapping of two affected siblings and three unaffected family members identified two candidate autozygous loci segregating with disease, 8q24.12-8q24.13 and 9q31.2-q33.1. Whole-exome sequence analysis identified a single rare homozygous missense sequence variant within this region, p.D82G. Although unaffected family members were heterozygous for this putative causal mutation, it was absent in 3,222 non-Parkinson's disease (PD) subjects of Pakistani heritage. Screening of 353 Australian PD cases, including 104 early-onset cases and 57 probands from multi-incident families, also did not identify additional carriers. Overexpression of wild-type and the variant CCN3 constructs in HEK293T cells identified an impaired section of the variant protein, alluding to potential mechanisms for disease. Further, qPCR analysis complemented previous microarray data suggesting mRNA expression of was downregulated in unrelated sporadic PD cases when compared to unaffected subjects. These data indicate a role for CCN3 in parkinsonism, both in this family as well as sporadic PD cases; however, the specific mechanisms require further investigation. Additionally, further screening of the rural community where the family resided is warranted to assess the local frequency of the variant. Overall, this study highlights the value of investigating underrepresented and isolated affected families for novel putative parkinsonism genes.
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http://dx.doi.org/10.3389/fneur.2020.00331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242651PMC
May 2020

A Grand Challenge. 3. Unbiased Phenotypic Function of Metabolites from Australia Plants and against Parkinson's Disease.

J Nat Prod 2020 05 6;83(5):1440-1452. Epub 2020 May 6.

Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.

As part of a continuing research program aiming to identify chemical probes to interrogate Parkinson's disease (PD), we have investigated the Australian plants and . The chemical investigations of resulted in the isolation of four new alkaloids, β-lumicolchicosides A-C (-) and γ-lumicolchicoside A (), together with four lumicolchicine derivatives (-) and six colchicine analogues (-) as known structures. The chemical investigations of resulted in the isolation of four new benzoquinolizidine -oxides, tubulosine -oxide (), isotubulosine -oxide (), 9-demethyltubulosine -oxide (), and 9-demethylisotubulosine -oxide (), together with five known benzoquinolizidine alkaloids (-). The chemical structures of the new compounds (- and -) were characterized unambiguously by extensive analysis of their NMR and MS data. Unbiased multidimensional profiling was used to investigate the phenotypic profiles of all of the metabolites. The results show that the lead probes have different effects on cellular organelles that are implicated in PD in patient-derived cells.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00880DOI Listing
May 2020

Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.

Nat Commun 2020 03 6;11(1):1238. Epub 2020 Mar 6.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
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http://dx.doi.org/10.1038/s41467-020-15065-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060318PMC
March 2020

O-GlcNAcylation of truncated NAC segment alters peptide-dependent effects on α-synuclein aggregation.

Bioorg Chem 2020 01 9;94:103389. Epub 2019 Nov 9.

School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia; Quality Use of Medicines Network, Griffith University, Gold Coast, QLD 4222, Australia. Electronic address:

Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.
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http://dx.doi.org/10.1016/j.bioorg.2019.103389DOI Listing
January 2020

Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein.

Acta Pharmacol Sin 2020 Apr 4;41(4):483-498. Epub 2019 Oct 4.

Griffith Institute for Drug Discovery, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan, QLD, 4111, Australia.

Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson's disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.
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http://dx.doi.org/10.1038/s41401-019-0304-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470848PMC
April 2020

Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing.

Genome Med 2019 08 23;11(1):54. Epub 2019 Aug 23.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.

Background: DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association.

Methods: In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues.

Results: We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor.

Conclusions: This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.
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http://dx.doi.org/10.1186/s13073-019-0667-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708158PMC
August 2019

Identification of a New α-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening.

ACS Chem Neurosci 2019 06 4;10(6):2683-2691. Epub 2019 Jun 4.

Griffith Institute for Drug Discovery , Griffith University , Don Young Road , Nathan , QLD 4111 , Australia.

The aggregation of disordered α-synuclein protein is pathogenically connected with Parkinson's disease. Therefore, discovering molecules that can inhibit the misfolding and aggregation of α-synuclein is an active research area in PD drug development. A key property of such required therapeutic agents is specific binding to the target protein. Mass spectrometry allows rapid detection of direct interactions between molecules and proteins and is an ideal technique for discovering specific α-synuclein binders. Here, by setting up an automated mass spectrometry-based screening system, we were able to screen over 2500 compounds and identify a new α-synuclein inhibitor, 3-[(3-methoxyphenyl)carbamoyl]-7-[( E)-2-phenylethenyl]-4,7-dihydropyrazolo [1,5- a]pyrimidine-5-carboxylic acid (compound 2). This compound not only significantly inhibits the misfolding and aggregation of α-synuclein and protects neuroblastoma cells from α-synuclein toxicity, but also has a more specific binding site compared with positive controls. Our work for the first time reports the inhibition of compound 2 on α-synuclein aggregation and also consolidates the capability of mass spectrometry to discover α-synuclein aggregation inhibitors.
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http://dx.doi.org/10.1021/acschemneuro.9b00092DOI Listing
June 2019

O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease.

ACS Chem Neurosci 2019 05 26;10(5):2209-2221. Epub 2019 Apr 26.

Menzies Health Institute Queensland , Griffith University , Gold Coast 4222 , Australia.

Post-translational modifications (PTMs) of proteins are becoming the focus of intense research due to their implications in a broad spectrum of neurodegenerative diseases. Various PTMs have been identified to alter the toxic profiles of proteins which play critical roles in disease etiology. In Alzheimer's disease (AD), dysregulated phosphorylation is reported to promote pathogenic processing of the microtubule-associated tau protein. Among the PTMs, the enzymatic addition of N-acetyl-d-glucosamine (GlcNAc) residues to Ser/Thr residues is reported to deliver protective effects against the pathogenic processing of both amyloid precursor protein (APP) and tau. Modification of tau with as few as one single O-GlcNAc residue inhibits its toxic self-assembly. This modification also has the same effect on the assembly of the Parkinson's disease (PD) associated α-synuclein (ASyn) protein. In fact, O-GlcNAcylation ( O-linked GlcNAc modification) affects the processing of numerous proteins implicated in AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) in a similar manner. As such, manipulation of a protein's O-GlcNAcylation status has been proposed to offer therapeutic routes toward addressing multiple neurodegenerative pathologies. Here we review the various effects that O-GlcNAc modification, and its modulated expression, have on pathogenically significant proteins involved in neurodegenerative disease.
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http://dx.doi.org/10.1021/acschemneuro.9b00143DOI Listing
May 2019

Depression symptomatology correlates with event-related potentials in Parkinson's disease: An affective priming study.

J Affect Disord 2019 02 13;245:897-904. Epub 2018 Nov 13.

UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane & Women's Hospital, Herston, Brisbane QLD4029, Australia; School of Health & Rehabilitation Sciences, The University of Queensland, St Lucia, Brisbane QLD4067, Australia.

Background: Depression is a predominant non-motor symptom of Parkinson's disease (PD), which is often under recognised and undertreated. To improve identification of depression in PD it is imperative to examine objective brain-related markers. The present study addresses this gap by using electroencephalography (EEG) to evaluate the processing of emotionally valanced words in PD.

Methods: Fifty non-demented PD patients, unmedicated for depression or anxiety, completed an affective priming task while EEG was simultaneously recorded. Prime and target word pairs of negative or neutral valence were presented at a short 250 ms stimulus onset asynchrony. Participants were asked to evaluate the valence of the target word by button press. Depression was measured using an established rating scale. Repeated measures analysis of covariance and correlational analyses were performed to examine whether event-related potentials (ERP) varied as a function of depression scores.

Results: Key ERP findings reveal reduced responses in parietal midline P300, N400 and Late Positive Potential (LPP) difference waves between congruent and incongruent neutral targets in patients with higher depression scores.

Limitations: Comparisons of ERPs were limited by insufficient classification of participants with and without clinical depression. A majority of PD patients who had high depression scores were excluded from the analysis as they were receiving antidepressant and/or anxiolytic medications which could interfere with ERP sensitivity.

Conclusions: The present study suggests that the Pz-P300, N400 and LPP are ERP markers relates to emotional dysfunction in PD. These findings thus advance current knowledge regarding the neurophysiological markers of a common neuropsychiatric deficit in PD.
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http://dx.doi.org/10.1016/j.jad.2018.11.094DOI Listing
February 2019

Wild-type and mutant (G2019S) leucine-rich repeat kinase 2 (LRRK2) associate with subunits of the translocase of outer mitochondrial membrane (TOM) complex.

Exp Cell Res 2019 02 28;375(2):72-79. Epub 2018 Dec 28.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Leucine-rich repeat kinase 2 (LRRK2) is important in various cellular processes including mitochondrial homeostasis and mutations in this gene lead to Parkinson's disease (PD). However, the full spectrum of LRRK2's functions remain to be elucidated. The translocase of outer mitochondrial membrane (TOM) complex is essential for the import of almost all nuclear-encoded mitochondrial proteins and is fundamental for cellular survival. Using co-immunoprecipitation, super-resolution structured illumination microscopy (SR-SIM), and 3D virtual reality (VR) assisted co-localization analysis techniques we show that wild-type and mutant (G2019S) LRRK2 associate and co-localize with subunits of the TOM complex, either under basal (dimethyl sulfoxide, DMSO) or stress-induced (carbonyl cyanide m-chlorophenyl hydrazine, CCCP) conditions. Interestingly, LRRK2 interacted with TOM40 under both DMSO and CCCP conditions, and when the PD causing mutation, G2019S was introduced, the association was not altered. Moreover, overexpression of G2019S LRRK2 resulted in the formation of large, perinuclear aggregates that co-localized with the TOM complex. Taken together, this is the first study to show that both WT and mutant LRRK2 associate with the TOM complex subunits. These findings provide additional evidence for LRRK2's role in mitochondrial function which has important implications for its role in PD pathogenesis.
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http://dx.doi.org/10.1016/j.yexcr.2018.12.022DOI Listing
February 2019

Evidence for the role of FMR1 gray zone alleles as a risk factor for parkinsonism in females.

Mov Disord 2018 07;33(7):1178-1181

Department of Medicine (Neuroscience), Monash University (Alfred Hospital Campus), Melbourne, VIC, Australia.

Background and Objective There is convincing evidence that small CGG expansion (41-54 repeats): FMR1 "gray zone" alleles (GZ) contribute to the risk of parkinsonism in males, but there is insufficient corresponding data in females. This study intends to fill this gap. Methods We screened whole-blood-derived DNA from a cohort of 601 females diagnosed with idiopathic PD, and from dry Guthrie blood spots from a local sample of 1,005 female newborns (population controls), for the size of the FMR1 CGG repeat using a PCR technique. Results We found a significant excess (8.2%) of GZ carriers compared with 5.2% in the control sample, with a P value of 0.009 for the difference in proportions. Conclusion FMR1 gray zone alleles are a significant risk factor for parkinsonism in females. These population data and occasional reports of FXTAS-like or parkinsonian manifestations in carriers suggest possible mechanisms whereby the effects of these alleles synergize with the existing pathologies underpinning parkinsonism. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116531PMC
July 2018

How Well Do Caregivers Detect Depression and Anxiety in Patients With Parkinson Disease?

J Geriatr Psychiatry Neurol 2018 09 2;31(5):227-236. Epub 2018 Aug 2.

1 School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.

Depression and anxiety are prevalent in Parkinson disease (PD) yet underrecognized in clinical practice. Caregiver reports are frequently utilized to aid in the assessment of neuropsychiatric symptoms but little is known about caregivers' ability to recognize them in patients with PD. This study sought to examine the accuracy of caregiver reports. Eighty patient-caregiver dyads were involved. Accuracy of caregiver recognition was assessed by examining the level of agreement between caregiver ratings on the Neuropsychiatric Inventory and patients' diagnosis of depression and anxiety on the Mini-International Neuropsychiatric Interview (MINI)-Plus. The agreement between caregiver report and MINI-Plus diagnosis was low for both depression (6.3%) and anxiety (17.5%). The presence of depression was overreported, while anxiety was largely underestimated by caregivers. Caregiver distress significantly predicted inaccurate caregiver identification of depression ( R = .51, P < .001) and anxiety ( R = .08, P < .05). Results indicate that caregivers may be poor at recognizing depression and anxiety in patients with PD. Utilization of caregiver report should take into account potential biases that affect caregiver judgment.
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http://dx.doi.org/10.1177/0891988718788641DOI Listing
September 2018

Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space.

J Med Chem 2018 Aug 27;61(15):6609-6628. Epub 2018 Jul 27.

Griffith Institute for Drug Discovery , Griffith University , Brisbane , QLD 4111 , Australia.

A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00194DOI Listing
August 2018

Pipeline to gene discovery - Analysing familial Parkinsonism in the Queensland Parkinson's Project.

Parkinsonism Relat Disord 2018 04 3;49:34-41. Epub 2018 Jan 3.

Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, Australia. Electronic address:

Introduction: Family based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register.

Method: The presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725. Whole exome sequencing (WES) was performed on eighteen probands from multiplex families.

Results: The QPP contains seventeen incidences of confirmed monogenic forms of PD, including LRRK2 p.G2019S, VPS35 p.D620N, SNCA duplications and PARK2 p.G430D (hom) & exon 4 deletion (hom). Of these seventeen, five belong to multi-incident families, while another eight have a family history of at least one other case of PD. In additional families, WES did not identify known forms of monogenic Parkinsonism; however, three heterozygous mutations in PARK2, p.R275W, p.Q34fs, and a 40bp deletion in exon 3 were identified. Of these three mutations, only the 40bp deletion segregated with disease in a dominant inheritance pattern.

Conclusion: Eighteen probands have screened negative for known CNVs and mutations that cause clear monogenic forms of PD. Each family is a candidate for further genetic analysis to identify genetic variants segregating with disease. The families enrolled in the QPP provide a useful resource to aid in identifying novel forms of monogenic PD.
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http://dx.doi.org/10.1016/j.parkreldis.2017.12.033DOI Listing
April 2018

Mini-review on initiatives to interfere with the propagation and clearance of alpha-synuclein in Parkinson's disease.

Transl Neurodegener 2017 20;6:33. Epub 2017 Dec 20.

Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD Australia.

In this mini-review, we summarize recent findings relating to the prion-like propagation of α-synuclein (α-syn) and the development of novel therapeutic strategies to target synucleinopathy in Parkinson's disease (PD). We link the Braak's staging hypothesis of PD with the recent evidence from in-vivo and in-vitro studies for the prion-like cell-to-cell propagation of α-syn (via exocytosis and endocytosis). The classical accumulation of aggregated α-syn in PD may result from an increased production or a failure in the mechanisms of clearance of α-syn. We discuss novel agents, currently in clinical trial for PD including the ones that impact the aggregation of α-syn and others that interfere with α-syn endocytosis as a means to target the progression of the disease.
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http://dx.doi.org/10.1186/s40035-017-0104-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738184PMC
December 2017

Dexamethasone Inhibits Copper-Induced Alpha-Synuclein Aggregation by a Metallothionein-Dependent Mechanism.

Neurotox Res 2018 02 24;33(2):229-238. Epub 2017 Oct 24.

Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.

Intracellular aggregates of α-synuclein are the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), being linked to neurotoxicity. Multiple triggers of α-synuclein aggregation have been implicated, including raised copper. The potential protective role of the endogenous copper-/zinc-binding proteins, metallothioneins (MT), has been explored in relation to copper-induced α-synuclein aggregation. Up-regulated endogenous expression of MT was induced in SHSY-5Y cells by the synthetic glucocorticoid analogue, dexamethasone. After treatment to induce endogenous MT expression, immunofluorescence confocal microscopy was used to quantify protein aggregates in cells with/without copper treatment. MT induction resulted in significant (p < 0.01), dose-dependent up-regulation of MT expression and significant reduction in Cu-dependent α-synuclein intracellular aggregates (p < 0.01) that could be suppressed by MT-specific siRNA. Ubiquitous (MT-2) and brain-specific (MT-3) isoforms were investigated by transient transfection of the GFP-fusion proteins, observing equivalent α-synuclein aggregate suppression by each. These studies indicate MT induction could have potential in PD/DLB neuroprotective therapy by suppressing α-synuclein aggregation.
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http://dx.doi.org/10.1007/s12640-017-9825-7DOI Listing
February 2018
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