David Allsop | The University of Sydney (original) (raw)
Papers by David Allsop
The FASEB Journal, 2003
Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fib... more Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fibrillar aggregates of α-synuclein protein (α-syn) inside brain cells. It is likely that the formation of α-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, because two different mutations in the gene encoding α-syn have been found in inherited forms of PD. α-Syn is mainly expressed by neuronal cells and is generally considered to exist as a cytoplasmic protein. Here, we report the unexpected identification of α-syn in conditioned culture media from untransfected and α-syn-transfected human neuroblastoma cells, as well as in human cerebrospinal fluid and blood plasma. The method used was immunocapture by using anti-α-syn antibodies coupled to magnetic beads, followed by detection on Western blots. In all cases, α-syn was identified as a single 15 kDa band, which co-migrated with a recombinant form of the protein and reacted with five different antibodies to α-syn. Our findings suggest that cells normally secrete α-syn into their surrounding media, both in vitro and in vivo. The detection of extracellular α-syn and/or its modified forms in body fluids, particularly in human plasma, offers new opportunities for the development of diagnostic tests for PD and related diseases.
Neurobiology of Aging, 2004
Background: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy... more Background: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are all neurodegenerative diseases, collectively called 'synucleinopathies', which are characterised by the accumulation of fibrillar aggregates of c~ -synuclein protein (c~-syn) inside brain cells. It is likely that the formation of c~-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, since three different mutations in the gene encoding c<-syn have been found in inherited forms of PD. It has been reported that lesions similar to those found in the PD brains can be created in transgenic animals over-express human ct-syn, and progressively develop a loss of dopaminergic cells together with motor abnormalities. Objective(s): Inhibiting and/or reversing ct-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. Methods: We synthesised a library of overlapping 7-met peptides spanning the entire et-syn sequence, and identified the binding region responsible for its self-association. Results:
Human pathology, 1990
To clarify early pathologic changes in Alzheimer's disease, the brains from two cases from a ... more To clarify early pathologic changes in Alzheimer's disease, the brains from two cases from a single family with this disease were examined. A mother who died at age 75 with severe dementia showed an abundance of typical senile plaques, neurofibrillary tangles, and cerebrovascular amyloidosis. The senile plaque and cerebrovascular amyloid were strongly immunoreactive to anti-beta protein antibody. Her son manifested erratic and bizarre behavior, and was suspected of having committed suicide at age 52. His brain weight and macroscopic observations were normal; however, Bielschowsky's silver impregnation and methenamine silver stains showed numerous argyrophilic plaque-like lesions in the neocortex. They were weakly immunolabeled by anti-beta protein antibody, but lacked any abnormal neurites of Congophilic amyloid deposits. These lesions resembled the "type 3" immunoreactive lesions (previously reported by us in Alzheimer's disease and Down's syndrome) which ...
Neurobiology of Aging, 2004
15-fold increase in xCT RNA levels in the cell. Furthermore, we show that the anti-inflammatory i... more 15-fold increase in xCT RNA levels in the cell. Furthermore, we show that the anti-inflammatory interleukins (IL)-4, IL-10 and IL-13 are capable of attenuating the AIMnduced microglial glutamate secretion by more than half. Conclusions: Given these results on glutamate release and xCT gene regulation together with our earlier reports that IL-4, IL-10, and IL-13 are found in the brain and suppress cytokine and chemokine release from A~activated microglia, we propose that glutamatergic disruption in AD may in part be mediated by chronic inflammation and microglial-derived glutamate release inadequately countered by endogenous anti-inflammatory cytokines.
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents, 2003
The deposition of abnormal protein fibrils is a prominent pathological feature of many different ... more The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the β-amyloid (Aβ) peptide, which accumulates in the brain in Alzheimer's disease, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown that solutions of Aβ liberate hydroxyl radicals when incubated in vitro, upon the addition of small amounts of Fe(II). We have also obtained similar results with α-synuclein, which accumulates in Lewy bodies in Parkinson's disease, and with the PrP (106-126) toxic fragment of the prion protein. It is becoming clear that some transition metal ions, especially Fe(III) and Cu(II), can bind to these aggregating peptides, and that some of them can reduce the oxidation state of Fe(III) and/or Cu(II). The data suggest that hydrogen peroxide accumulates during incubation of these various proteins and peptides, and is subsequently converted to hydroxyl radicals in the presence of redox-active transition metal ions. Consequently, a fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of ROS during formation of the abnormal protein aggregates.
Tohoku J Exp Med, 1994
An immunohistochemical study was carried out on the brains of 7 adult Down's syndrome cas... more An immunohistochemical study was carried out on the brains of 7 adult Down's syndrome cases (ages 31 to 62) using antibodies to beta-protein, beta-amyloid protein precursor and tau-protein. Variable forms of beta-protein deposited lesions (including senile plaques and cerebrovascular amyloidosis) were observed in extensive areas of the neocortex of all cases and coexistence of both beta-protein amyloid fibrils and beta-amyloid protein precursors was also seen in some of these lesions. Moreover, 3 cases at an advanced stage showed a few plaque-like lesions with beta-protein immunoreactivity in the white matter. The following temporal morphological change is suggested for the pathogenesis of Alzheimer's disease: senile plaque undergo sequential structural changes and beta-protein amyloid deposits in the form of "early plaque" precede the development of tau-immunoreactive neurofibrillary degeneration.
PLoS ONE, 2012
Background and Aims: Questions over the clinical significance of cannabis withdrawal have hindere... more Background and Aims: Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.
Drug and Alcohol Dependence, 2014
Trends in Pharmacological Sciences, 1991
While there may be many causes of Alzheimer's disease (AD), the same pathological sequenc... more While there may be many causes of Alzheimer's disease (AD), the same pathological sequence of events, described here by John Hardy and David Allsop, is likely to occur in all cases. The recent discovery of a pathogenic mutation in the beta-amyloid precursor protein (APP) gene on chromosome 21 suggests that APP Mismetabolism and beta-amyloid deposition are the primary events in the disease process. The occurrence of AD in Down syndrome is consistent with this hypothesis. The pathological cascade for the disease process is most likely to be: beta-amyloid deposition----tau phosphorylation and tangle formation----neuronal death. The development of a biochemical understanding of this pathological cascade will facilitate rational design of drugs to intervene in this process.
The FASEB Journal, 2006
To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on bioch... more To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). ␣-Synuclein (␣-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding ␣-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of ␣-syn into insoluble aggregates. We recently reported the presence of ␣-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether ␣-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of ␣-syn. Using this ELISA, we report the presence of significantly elevated
The American Naturalist, 2005
Recent comparative studies across sex-changing animals have found that the relative size and age ... more Recent comparative studies across sex-changing animals have found that the relative size and age at sex change are strikingly invariant. In particular, 91%-97% of the variation in size at sex change across species can be explained by the simple rule that individuals change sex when they reach 72% of their maximum body size. However, this degree of invariance is surprising and has proved controversial. In particular, it is not clear why this result should hold, given that there is considerable biological variation across species in factors that can influence the evolutionarily stable timing of sex change. Our overall aim here is to explain this result and determine the implications for other life-history variables. Specifically, we use a combination of approaches to formalize and make explicit previous analytical theory in this area, examine the robustness of the empirical invariance result, and carry out sensitivity analyses to determine what the empirical data imply about the mean value and variation in several key life-history variables.
Neurobiology of Disease, 2012
Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndrom... more Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p b 0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p b 0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.
The FASEB Journal, 2003
Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fib... more Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fibrillar aggregates of α-synuclein protein (α-syn) inside brain cells. It is likely that the formation of α-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, because two different mutations in the gene encoding α-syn have been found in inherited forms of PD. α-Syn is mainly expressed by neuronal cells and is generally considered to exist as a cytoplasmic protein. Here, we report the unexpected identification of α-syn in conditioned culture media from untransfected and α-syn-transfected human neuroblastoma cells, as well as in human cerebrospinal fluid and blood plasma. The method used was immunocapture by using anti-α-syn antibodies coupled to magnetic beads, followed by detection on Western blots. In all cases, α-syn was identified as a single 15 kDa band, which co-migrated with a recombinant form of the protein and reacted with five different antibodies to α-syn. Our findings suggest that cells normally secrete α-syn into their surrounding media, both in vitro and in vivo. The detection of extracellular α-syn and/or its modified forms in body fluids, particularly in human plasma, offers new opportunities for the development of diagnostic tests for PD and related diseases.
Neurobiology of Aging, 2004
Background: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy... more Background: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are all neurodegenerative diseases, collectively called 'synucleinopathies', which are characterised by the accumulation of fibrillar aggregates of c~ -synuclein protein (c~-syn) inside brain cells. It is likely that the formation of c~-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, since three different mutations in the gene encoding c<-syn have been found in inherited forms of PD. It has been reported that lesions similar to those found in the PD brains can be created in transgenic animals over-express human ct-syn, and progressively develop a loss of dopaminergic cells together with motor abnormalities. Objective(s): Inhibiting and/or reversing ct-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. Methods: We synthesised a library of overlapping 7-met peptides spanning the entire et-syn sequence, and identified the binding region responsible for its self-association. Results:
Human pathology, 1990
To clarify early pathologic changes in Alzheimer's disease, the brains from two cases from a ... more To clarify early pathologic changes in Alzheimer's disease, the brains from two cases from a single family with this disease were examined. A mother who died at age 75 with severe dementia showed an abundance of typical senile plaques, neurofibrillary tangles, and cerebrovascular amyloidosis. The senile plaque and cerebrovascular amyloid were strongly immunoreactive to anti-beta protein antibody. Her son manifested erratic and bizarre behavior, and was suspected of having committed suicide at age 52. His brain weight and macroscopic observations were normal; however, Bielschowsky's silver impregnation and methenamine silver stains showed numerous argyrophilic plaque-like lesions in the neocortex. They were weakly immunolabeled by anti-beta protein antibody, but lacked any abnormal neurites of Congophilic amyloid deposits. These lesions resembled the "type 3" immunoreactive lesions (previously reported by us in Alzheimer's disease and Down's syndrome) which ...
Neurobiology of Aging, 2004
15-fold increase in xCT RNA levels in the cell. Furthermore, we show that the anti-inflammatory i... more 15-fold increase in xCT RNA levels in the cell. Furthermore, we show that the anti-inflammatory interleukins (IL)-4, IL-10 and IL-13 are capable of attenuating the AIMnduced microglial glutamate secretion by more than half. Conclusions: Given these results on glutamate release and xCT gene regulation together with our earlier reports that IL-4, IL-10, and IL-13 are found in the brain and suppress cytokine and chemokine release from A~activated microglia, we propose that glutamatergic disruption in AD may in part be mediated by chronic inflammation and microglial-derived glutamate release inadequately countered by endogenous anti-inflammatory cytokines.
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents, 2003
The deposition of abnormal protein fibrils is a prominent pathological feature of many different ... more The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the β-amyloid (Aβ) peptide, which accumulates in the brain in Alzheimer's disease, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown that solutions of Aβ liberate hydroxyl radicals when incubated in vitro, upon the addition of small amounts of Fe(II). We have also obtained similar results with α-synuclein, which accumulates in Lewy bodies in Parkinson's disease, and with the PrP (106-126) toxic fragment of the prion protein. It is becoming clear that some transition metal ions, especially Fe(III) and Cu(II), can bind to these aggregating peptides, and that some of them can reduce the oxidation state of Fe(III) and/or Cu(II). The data suggest that hydrogen peroxide accumulates during incubation of these various proteins and peptides, and is subsequently converted to hydroxyl radicals in the presence of redox-active transition metal ions. Consequently, a fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of ROS during formation of the abnormal protein aggregates.
Tohoku J Exp Med, 1994
An immunohistochemical study was carried out on the brains of 7 adult Down's syndrome cas... more An immunohistochemical study was carried out on the brains of 7 adult Down's syndrome cases (ages 31 to 62) using antibodies to beta-protein, beta-amyloid protein precursor and tau-protein. Variable forms of beta-protein deposited lesions (including senile plaques and cerebrovascular amyloidosis) were observed in extensive areas of the neocortex of all cases and coexistence of both beta-protein amyloid fibrils and beta-amyloid protein precursors was also seen in some of these lesions. Moreover, 3 cases at an advanced stage showed a few plaque-like lesions with beta-protein immunoreactivity in the white matter. The following temporal morphological change is suggested for the pathogenesis of Alzheimer's disease: senile plaque undergo sequential structural changes and beta-protein amyloid deposits in the form of "early plaque" precede the development of tau-immunoreactive neurofibrillary degeneration.
PLoS ONE, 2012
Background and Aims: Questions over the clinical significance of cannabis withdrawal have hindere... more Background and Aims: Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.
Drug and Alcohol Dependence, 2014
Trends in Pharmacological Sciences, 1991
While there may be many causes of Alzheimer's disease (AD), the same pathological sequenc... more While there may be many causes of Alzheimer's disease (AD), the same pathological sequence of events, described here by John Hardy and David Allsop, is likely to occur in all cases. The recent discovery of a pathogenic mutation in the beta-amyloid precursor protein (APP) gene on chromosome 21 suggests that APP Mismetabolism and beta-amyloid deposition are the primary events in the disease process. The occurrence of AD in Down syndrome is consistent with this hypothesis. The pathological cascade for the disease process is most likely to be: beta-amyloid deposition----tau phosphorylation and tangle formation----neuronal death. The development of a biochemical understanding of this pathological cascade will facilitate rational design of drugs to intervene in this process.
The FASEB Journal, 2006
To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on bioch... more To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). ␣-Synuclein (␣-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding ␣-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of ␣-syn into insoluble aggregates. We recently reported the presence of ␣-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether ␣-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of ␣-syn. Using this ELISA, we report the presence of significantly elevated
The American Naturalist, 2005
Recent comparative studies across sex-changing animals have found that the relative size and age ... more Recent comparative studies across sex-changing animals have found that the relative size and age at sex change are strikingly invariant. In particular, 91%-97% of the variation in size at sex change across species can be explained by the simple rule that individuals change sex when they reach 72% of their maximum body size. However, this degree of invariance is surprising and has proved controversial. In particular, it is not clear why this result should hold, given that there is considerable biological variation across species in factors that can influence the evolutionarily stable timing of sex change. Our overall aim here is to explain this result and determine the implications for other life-history variables. Specifically, we use a combination of approaches to formalize and make explicit previous analytical theory in this area, examine the robustness of the empirical invariance result, and carry out sensitivity analyses to determine what the empirical data imply about the mean value and variation in several key life-history variables.
Neurobiology of Disease, 2012
Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndrom... more Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p b 0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p b 0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.