Biology subjects

Gregory, J. M.

Publications and source records attributed to Gregory, J. M..

3 recordsLinked to original sources

bioRxiv2023

Distinct neuroinflammatory signatures exist across genetic and sporadic ALS cohorts

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia (FTD), with patients sometimes experiencing elements of both conditions (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion (HRE), the factors influencing where an individual may lie on this spectrum require further characterisation. Here, using NanoString molecular barcoding with a panel of 770 neuroinflammatory genes, we interrogate inflammatory dysregulation at the level of gene expression. We identified 20 dysregulated neuroinflammatory genes in the motor cortex of deeply clinically phenotyped C9-ALS post-mortem cases, with enrichment of microglial and inflammatory response gene sets. Our analyses also revealed two distinct ALS-related neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5 and BDNF. FKBP5 and its signalling partner, NF-{kappa}B, appeared to have a cell-type-specific staining distribution, with activated (i.e., nuclear) NF-{kappa}B immunoreactivity in C9-ALS. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope in situ hybridisation. Finally, we compared NPS between C9-ALS cases and those from deeply clinically phenotyped sporadic ALS (sALS) and SOD1-ALS cohorts, with NPS1 and NPS2 appearing across all cohorts. A subset of these signatures was also detected in publicly available RNA-sequencing data from independent C9-ALS and sALS cohorts, underscoring the relevance of these pathways across cohorts. Our findings highlight the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within genetic and sporadic cohorts.

neuroscience↗

bioRxiv2022

pTDP-43 aggregates accumulate in the gut and other non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis

ObjectiveNeurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and non-central nervous system (CNS) manifestations, particularly gastrointestinal (GI) symptoms, are common. Our objective was to understand the systemic distribution of pathology in archived non-CNS tissues, taken as part of routine clinical practice during life from people with ALS. DesignWe requested all surgical specimens of non-CNS tissue taken during life from 48 people with ALS, for whom evidence of the characteristic proteinopathy associated with ALS had been identified in the CNS after death (i.e., the pathological cytoplasmic accumulation of phosphorylated TDP-43 (pTDP-43) aggregates). Of the 48 patients, 13 had sufficient tissue for evaluation: 12 patients with sporadic ALS and 1 patient with a C9orf72 hexanucleotide repeat expansion. The final cohort consisted of 68 formalin-fixed paraffin embedded tissue samples from 22 surgical cases (some patients having more than one case over their lifetimes), representing 8 organ systems, which we examined for evidence of pTDP-43 pathology. The median age of tissue removal was 62.4 years old and median tissue removal to death was 6.3 years. ResultsWe identified pTDP-43 aggregates in multiple cell types of the GI tract (i.e., colon and gallbladder), including macrophages and dendritic cells within the lamina propria, as well as neuronal and glial cells of the myenteric plexus. Aggregates were also noted within lymph node parenchyma, blood vessel endothelial cells, and chondrocytes. We note that in all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis (median=3years) and, in some instances, preceded neurological symptom onset by more than 10 years. ConclusionThese data imply that patients with non-CNS symptoms may have occult protein aggregation that could be detected many years prior to neurological involvement. SummaryNeurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and non-central nervous system (CNS) manifestations, particularly gastrointestinal (GI) symptoms, are common. Our objective was to understand the systemic distribution of TDP-43 pathology in archived non-CNS tissues, taken as part of routine clinical practice during life from people with ALS. We identified pTDP-43 aggregates in multiple cell types of the GI tract (i.e., colon and gallbladder), and within lymph node parenchyma, blood vessel endothelial cells, and chondrocytes. We note that in all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis (median=24months) and, in some instances, preceded neurological symptom onset by more than 10years. These data imply that patients with non-CNS symptoms may have occult protein aggregation tha could be detected many years prior to neurological involvement. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/484805v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1f568c6org.highwire.dtl.DTLVardef@b1d99dorg.highwire.dtl.DTLVardef@45e643org.highwire.dtl.DTLVardef@1106d29_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Ante-mortem tissue cohort comprised of tissue taken from people with ALS demonstrates non-CNS accumulation of pTDP-43 aggregates prior to symptom onset. Schematic of workflow to identify pTDP-43 aggregates indicative of non-central nervous system (CNS) manifestations of ALS. Lower panel left: cartoon depicting organs and cell types that had evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue. Lower panel right: cartoon depicting organs with no evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue. C_FIG

neuroscience↗

bioRxiv2021

Random forest modelling of neuropathological features identifies microglial activation as an accurate pathological classifier of C9orf72-related amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are regarded as two ends of a pathogenetic spectrum, termed ALS-frontotemporal spectrum disorder (ALS-FTSD). However, it is currently difficult to predict where on the spectrum an individual will lie, especially for patients with C9orf72 hexanucleotide repeat expansions (HRE), a mutation associated with both ALS and FTD. It has been shown that both inflammation and protein misfolding influence aspects of ALS and ALS-FTSD disease pathogenesis, such as the manifestation or severity of motor or cognitive symptoms. Previous studies have highlighted markers which may influence C9orf72-associated disease presentation in a targeted fashion, though there has yet to be a systematic and quantitative assessment of common immunohistochemical markers to investigate the significance of these pathways in an unbiased manner. Here we report the first extensive digital pathological assessment with random forest modelling of pathological markers often used in neuropathology practice. This study profiles glial activation and protein misfolding in a cohort of deeply clinically profiled post-mortem tissue from patients with a C9orf72 HRE, who either met the criteria for a diagnosis of ALS or ALS-FTSD. We show that microglial immunohistochemical staining features, both morphological and spatial, are the best independent classifiers of disease status and that clinicopathological associations exist between microglial activation status and cognitive dysfunction in ALS-FTSD patients with C9orf72 HRE. Furthermore, we show that spatially resolved changes in FUS staining are also an accurate predictor of disease status, implying that liquid-liquid phase shift of this aggregation-prone RNA-binding protein may be important in ALS caused by a C9orf72 HRE. Our findings provide further support to the hypothesis of dysfunctional immune regulation and proteostasis in the pathogenesis of C9orf72 ALS and provide a framework for digital analysis of commonly used neuropathological stains as a tool to enrich our understanding of clinicopathological associations between cohorts.

neuroscience↗