Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects
In this study, we examined a cohort of ten NEM2 patients, each with unique pathogenic variants, aiming to understand their impact on mRNA, protein, and functional levels. Results show that pathogenic truncation variants affectNEB mRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with pathogenic splicing variants that are expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with either relatively normal or markedly reduced nebulin. We observed a positive relation...
Source: Acta Neuropathologica - April 18, 2024 Category: Neurology Source Type: research
Histologic correlates of “Choroidal abnormalities” in Neurofibromatosis type 1 (NF1)
We present the postmortem ocular pathology findings of an NF1 patient for whom c linical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melano cytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperp...
Source: Acta Neuropathologica - April 12, 2024 Category: Neurology Source Type: research
Rare genetic variation in fibronectin 1 (FN1) protects against APOE ε4 in Alzheimer’s disease
AbstractThe risk of developing Alzheimer ’s disease (AD) significantly increases in individuals carrying theAPOE ε4 allele. Elderly cognitively healthy individuals withAPOE ε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects ofAPOE ε4; however, these mechanisms are unknown. We hypothesized thatAPOE ε4 carriers without dementia might carry genetic variations that could protect them from developingAPOE ε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA...
Source: Acta Neuropathologica - April 10, 2024 Category: Neurology Source Type: research
Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype
AbstractMutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered ...
Source: Acta Neuropathologica - April 7, 2024 Category: Neurology Source Type: research
Regulated cell death and its role in Alzheimer ’s disease and amyotrophic lateral sclerosis
AbstractDespite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerou s individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is adde...
Source: Acta Neuropathologica - April 7, 2024 Category: Neurology Source Type: research
Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases
AbstractTranscription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis ofGBA-related and sporadic Parkinson ’s disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation inpost-mortem human brain of individuals with either incidental Lewy body disease (iLBD),GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB...
Source: Acta Neuropathologica - April 6, 2024 Category: Neurology Source Type: research
Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer ’s disease and related dementias
AbstractReactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer ’s disease (AD)—Aβ plaques and neurofibrillary tangles—and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO -B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell t...
Source: Acta Neuropathologica - April 3, 2024 Category: Neurology Source Type: research
Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer ’s disease reveals distinct sequential responses to Aβ and tau
This study provides a data resource that builds on our knowledge of myeloid cell contribution to AD by defining the heterogeneity of microglia and brain macrophages during both temporal and regiona l pathology aspects of AD progression at an unprecedented resolution. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 1, 2024 Category: Neurology Source Type: research
Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion
AbstractPrader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptom...
Source: Acta Neuropathologica - March 31, 2024 Category: Neurology Source Type: research
Correction to: MET receptor serves as a promising target in melanoma brain metastases
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 27, 2024 Category: Neurology Source Type: research
TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy
AbstractTMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (e...
Source: Acta Neuropathologica - March 25, 2024 Category: Neurology Source Type: research
A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin
AbstractPreclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects w...
Source: Acta Neuropathologica - March 25, 2024 Category: Neurology Source Type: research
Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice
AbstractTMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently,TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting i...
Source: Acta Neuropathologica - March 25, 2024 Category: Neurology Source Type: research
Correction: Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncted Abeta in sporadic Alzheimer disease cases and mouse models
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 25, 2024 Category: Neurology Source Type: research
Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies
AbstractNeurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,26...
Source: Acta Neuropathologica - March 23, 2024 Category: Neurology Source Type: research
