Biology subjects

Rogaeva, E.

Publications and source records attributed to Rogaeva, E..

8 recordsLinked to original sources

bioRxiv2026

Microvascular pathology of proteotoxic endothelial signature characterizes Progressive Supranuclear Palsy

Cerebrovascular pathology is increasingly implicated in neurodegenerative diseases, yet its pathomechanistic contribution remains poorly defined. Building on prior evidence of dysregulated iron and oxygen homeostasis in early-affected brain regions of progressive supranuclear palsy (PSP), we hypothesized that brain microvascular alterations may play an etiological role in select neurodegenerative proteinopathies. First, we conducted a systematic neuropathological evaluation of 178 brains from the University Health Network Neurodegenerative Brain Collection, including Alzheimers disease-related neuropathologic change (ADNC; n=30), Lewy body disease with high or intermediate ADNC (n=38) and low ADNC (n=16), multiple system atrophy (MSA; n=14), PSP (n=39), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP; n=10), and controls (n=31). Arteriolosclerosis, microinfarction, and calcification were assessed in the basal ganglia and frontal cortex. Iron burden was correlated by quantification of Perls staining in MSA and PSP, where vessel pathology was most severe. Single-nucleus RNA-sequencing (snRNA-seq) of frontal cortex tissue from control (n=5) and PSP (n=8) cases with varying arteriolosclerosis severity was performed to characterize the vascular transcriptome, with validation against an independent snRNA-seq evaluation of PSP (n= 11), Picks disease (n=9), AD (n=10), and control (n=10) brains. Histological analysis revealed disease-specific involvement of microvascular pathology in neurodegenerative diseases, identifying PSP to demonstrate most prominent and widespread vessel wall thickening across regions examined. Regression analysis using demographic, APOE and MAPT genetic risk status, and neuropathological features of cases corroborated the distinct association with PSP pathology. Elevated iron load in early affected regions of MSA and PSP brains correlated with greater vessel wall thickening, suggesting a possible pathomechanistic relationship between the two disease physiologies. snRNA-seq analysis of vascular transcriptome identified robust upregulation of heat shock proteins and hypoxia-related genes in PSP endothelial cells and pericytes across both datasets. Importantly, we found the proteotoxic signature to be strongly associated with higher vessel scores in PSP cases, linking microvascular morphology to endothelial dysfunction. Our comprehensive neuropathological evaluation coupled with correlative snRNA-seq analysis establish PSP-specific arteriolar thickening associated with endothelial proteotoxic state as a candidate pathogenic mechanism. The cerebral arteriolar unit represents a compelling therapeutic target for disease modification in PSP.

pathology↗

bioRxiv2025

Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy

ObjectivesProgressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. MethodsWe evaluated an autopsy confirmed PSP cohort (n=44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA/Tau peptide binding prediction and modelling of HLA Class II and Tau Peptide interactions. FindingsOdds ratio was 2.94 (95% CI 1.01 to 8.55; p=0.047) for DQB1*06:01 allele, and 2.59 (95% CI 1.39 to 4.83; p=0.0025) for the narcolepsy associated haplotype (DRB1*15:01DQB1*06:02). One patient with 4 repeat tau PSP type pathology was a carrier of the IgLON5-associated haplotype (DRB1*10:01DQB1*05:01). HLA/Tau peptide binding prediction and modelling of HLA Class II/Tau Peptide interactions revealed strong binding tau peptides but not the PSP protofilament fold for alleles DQA1*01:02DQB1*06:02 and DQA1*01:03DQB1*06:01. ConclusionOur study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.

immunology↗

bioRxiv2024

Lewy-MSA hybrid fold drives distinct neuronal a-synuclein pathology

The ordered assembly of -synuclein protein into filaments encoded by SNCA characterizes neurodegenerative diseases called synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal -synuclein pathology and multiple system atrophy (MSA) predominantly oligodendrocytic -synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that structures of -synuclein filaments from LBD differ from MSA and juvenile onset synucleinopathy (JOS) caused by a 21-nucleotide duplication in the second exon of one allele of SNCA gene 1-3. Importantly, a rare subtype of MSA, called atypical MSA4 shows abundant neuronal argyrophilic -synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that in addition to the MSA fold, -synuclein can form a new Lewy-MSA hybrid fold in the same brain region, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of -synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs) and conformational stability assay (CSA), are also linked to cytopathological differences (e.g. neuronal or oligodendroglial). We expand the current structure-based classification of -synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.

pathology↗

bioRxiv2024

C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate- sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/620312v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@154b23borg.highwire.dtl.DTLVardef@1814a6dorg.highwire.dtl.DTLVardef@13d713eorg.highwire.dtl.DTLVardef@d5d994_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2023

Single-nucleus multiomic atlas of frontal cortex in amyotrophic lateral sclerosis with a deep learning-based decoding of alternative polyadenylation mechanisms

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two age-related and fatal neurodegenerative disorders that lie on a shared disease spectrum. While both disorders involve complex interactions between neuronal and glial cells, the specific cell-type alterations and their contributions to disease pathophysiology remain incompletely understood. Here, we applied single-nucleus RNA sequencing of the orbitofrontal cortex, a region affected in ALS-FTLD, to map cell-type specific transcriptional signatures in C9orf72-related ALS (with and without FTLD) and sporadic ALS cases. Our findings reveal disease- and cell-type-specific transcriptional changes, with neurons exhibiting the most pronounced alterations, primarily affecting mitochondrial function, protein homeostasis, and chromatin remodeling. A comparison with independent datasets from different cortical regions of C9orf72 and sporadic ALS cases showed concordance in several pathways, with neuronal STMN2 and NEFL showing consistent up-regulation between brain regions and disease subtypes. We also interrogated alternative polyadenylation (APA) as an additional layer of transcriptional regulation, demonstrating that APA events are not correlated with identified gene expression changes. To interpret these events, we developed APA-Net, a deep learning model that integrates transcript sequences with RNA-binding protein expression profiles, revealing cell type-specific patterns of APA regulation. Our atlas illuminates cell type-specific pathomechanisms of ALS/FTLD, providing a valuable resource for further investigation.

neuroscience↗

bioRxiv2023

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

neuroscience↗

bioRxiv2018

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinsons disease (PD) or Alzheimers disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

neuroscience↗

bioRxiv2018

The relationship between brain atrophy and cognitive-behavioral symptoms in retired Canadian football players with multiple concussions

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance. Deformation-based morphometric confirmed smaller bilateral hippocampal volume that were associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.

neuroscience↗