BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dement... more BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jack...
Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has bee... more Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, ...
The definitive diagnosis of Alzheimer’s disease (AD) rests with post-mortem neuropathology despit... more The definitive diagnosis of Alzheimer’s disease (AD) rests with post-mortem neuropathology despite the advent of more sensitive scanning and the search for reliable biomarkers. Even though the classic neuropathological features of AD have been known for many years, it was only relatively recently that more sensitive immunohistochemistry for amyloid beta (Aβ) and hyperphosphorylated tau (HP-tau) replaced silver-staining techniques. However, immunohistochemistry against these and other proteins has not only allowed a more scientific evaluation of the pathology of AD but also revealed some mimics of HP-tau pathological patterns of AD, including age-related changes, argyrophilic grain disease and chronic traumatic encephalopathy. It also highlighted a number of cases of AD with significant additional pathology including Lewy bodies, phosphorylated TDP-43 (p-TDP-43) positive neuronal cytoplasmic inclusions and vascular pathology. This concomitant pathology can cause a number of challenge...
TDP-43 is a DNA/RNA binding protein, but whether its interactions with RNA are relevant to inclus... more TDP-43 is a DNA/RNA binding protein, but whether its interactions with RNA are relevant to inclusion formation in ALS is unclear. Chen et al. report that mutated forms of TDP-43 that are unable to bind RNA have an increased tendency to aggregate, and can mediate toxicity by sequestering wild-type TDP-43.
Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sc... more Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumul...
POSTER PRESENTATIONS P1 P1-001 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMANPET STUDYOFNOVEL I... more POSTER PRESENTATIONS P1 P1-001 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMANPET STUDYOFNOVEL IN VIVOMARKER OF HUMAN TRANSLATOR PROTEIN Zhen Fan, Paul Edison, Rebecca Atkinson, Grazia Daniela Femminella, Valeria Calsolaro, Adam Waldman, Chris J. Buckley, William Trigg, David J. Brooks, Rainer Hinz, Imperial College London, London, United Kingdom; GE Healthcare, Amersham, United Kingdom; GE Healthcare, Amersham, United Kingdom; University of Manchester, Manchester, United Kingdom. Contact e-mail: [email protected]
Neuropathology and applied neurobiology, Jan 5, 2015
A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited Frontotemporal deme... more A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited Frontotemporal dementia (bvFTD), and Motor Neurone disease (MND), though the pathological mechanism(s) underlying disease remains uncertain. Using antibodies to poly-GA, poly-GP, poly-GR poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NC...
Journal of neural transmission (Vienna, Austria : 1996), Jan 29, 2015
Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease ... more Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease cases. Fixed tissue employed for diagnosis is often not appropriate for research and frozen tissue is therefore made available. Many brain banks use a protocol where half the brain is fixed and half frozen. Recently a study has shown that there can be asymmetry in protein deposition between the hemispheres especially with tau and TDP-43. We aimed to test this hypothesis by prospectively taking bilateral cortical blocks from 30 brains on arrival, and immunostaining to assess the degree of asymmetry. In 6 out 14 cases of AD (Alzheimer's Disease) (Modified Braak Stage V-VI), there was some asymmetrical staining for tau. In 2 cases, there was moderate discrepancy for tau staining between left and right calcarine cortices. However, careful analysis in both these cases revealed discrepancies in tau staining in adjacent regions even on the same side. The α-synuclein staining showed asymmetr...
Recent epigenome-wide association studies in Alzheimer's disease have highlighted consistent ... more Recent epigenome-wide association studies in Alzheimer's disease have highlighted consistent robust neuropathology-associated DNA hypermethylation of the ankyrin 1 (ANK1) gene in the cortex. The extent to which altered ANK1 DNA methylation is also associated with other neurodegenerative diseases is not currently known. In the present study, we used bisulfite pyrosequencing to quantify DNA methylation across 8 CpG sites within a 118 bp region of the ANK1 gene across multiple brain regions in Alzheimer's disease, Vascular dementia, Dementia with Lewy bodies, Huntington's disease, and Parkinson's disease. We demonstrate disease-associated ANK1 hypermethylation in the entorhinal cortex in Alzheimer's disease, Huntington's disease, and Parkinson's disease, whereas in donors with Vascular dementia and Dementia with Lewy bodies, we observed elevated ANK1 DNA methylation only in individuals with coexisting Alzheimer's disease pathology. We did not observe any...
Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and fron... more Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain m...
BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dement... more BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jack...
Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has bee... more Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, ...
The definitive diagnosis of Alzheimer’s disease (AD) rests with post-mortem neuropathology despit... more The definitive diagnosis of Alzheimer’s disease (AD) rests with post-mortem neuropathology despite the advent of more sensitive scanning and the search for reliable biomarkers. Even though the classic neuropathological features of AD have been known for many years, it was only relatively recently that more sensitive immunohistochemistry for amyloid beta (Aβ) and hyperphosphorylated tau (HP-tau) replaced silver-staining techniques. However, immunohistochemistry against these and other proteins has not only allowed a more scientific evaluation of the pathology of AD but also revealed some mimics of HP-tau pathological patterns of AD, including age-related changes, argyrophilic grain disease and chronic traumatic encephalopathy. It also highlighted a number of cases of AD with significant additional pathology including Lewy bodies, phosphorylated TDP-43 (p-TDP-43) positive neuronal cytoplasmic inclusions and vascular pathology. This concomitant pathology can cause a number of challenge...
TDP-43 is a DNA/RNA binding protein, but whether its interactions with RNA are relevant to inclus... more TDP-43 is a DNA/RNA binding protein, but whether its interactions with RNA are relevant to inclusion formation in ALS is unclear. Chen et al. report that mutated forms of TDP-43 that are unable to bind RNA have an increased tendency to aggregate, and can mediate toxicity by sequestering wild-type TDP-43.
Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sc... more Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumul...
POSTER PRESENTATIONS P1 P1-001 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMANPET STUDYOFNOVEL I... more POSTER PRESENTATIONS P1 P1-001 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMANPET STUDYOFNOVEL IN VIVOMARKER OF HUMAN TRANSLATOR PROTEIN Zhen Fan, Paul Edison, Rebecca Atkinson, Grazia Daniela Femminella, Valeria Calsolaro, Adam Waldman, Chris J. Buckley, William Trigg, David J. Brooks, Rainer Hinz, Imperial College London, London, United Kingdom; GE Healthcare, Amersham, United Kingdom; GE Healthcare, Amersham, United Kingdom; University of Manchester, Manchester, United Kingdom. Contact e-mail: [email protected]
Neuropathology and applied neurobiology, Jan 5, 2015
A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited Frontotemporal deme... more A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited Frontotemporal dementia (bvFTD), and Motor Neurone disease (MND), though the pathological mechanism(s) underlying disease remains uncertain. Using antibodies to poly-GA, poly-GP, poly-GR poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NC...
Journal of neural transmission (Vienna, Austria : 1996), Jan 29, 2015
Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease ... more Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease cases. Fixed tissue employed for diagnosis is often not appropriate for research and frozen tissue is therefore made available. Many brain banks use a protocol where half the brain is fixed and half frozen. Recently a study has shown that there can be asymmetry in protein deposition between the hemispheres especially with tau and TDP-43. We aimed to test this hypothesis by prospectively taking bilateral cortical blocks from 30 brains on arrival, and immunostaining to assess the degree of asymmetry. In 6 out 14 cases of AD (Alzheimer's Disease) (Modified Braak Stage V-VI), there was some asymmetrical staining for tau. In 2 cases, there was moderate discrepancy for tau staining between left and right calcarine cortices. However, careful analysis in both these cases revealed discrepancies in tau staining in adjacent regions even on the same side. The α-synuclein staining showed asymmetr...
Recent epigenome-wide association studies in Alzheimer's disease have highlighted consistent ... more Recent epigenome-wide association studies in Alzheimer's disease have highlighted consistent robust neuropathology-associated DNA hypermethylation of the ankyrin 1 (ANK1) gene in the cortex. The extent to which altered ANK1 DNA methylation is also associated with other neurodegenerative diseases is not currently known. In the present study, we used bisulfite pyrosequencing to quantify DNA methylation across 8 CpG sites within a 118 bp region of the ANK1 gene across multiple brain regions in Alzheimer's disease, Vascular dementia, Dementia with Lewy bodies, Huntington's disease, and Parkinson's disease. We demonstrate disease-associated ANK1 hypermethylation in the entorhinal cortex in Alzheimer's disease, Huntington's disease, and Parkinson's disease, whereas in donors with Vascular dementia and Dementia with Lewy bodies, we observed elevated ANK1 DNA methylation only in individuals with coexisting Alzheimer's disease pathology. We did not observe any...
Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and fron... more Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain m...
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