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

Gene transcript fusions are associated with clinical outcomes and molecular groups of meningiomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 20, 2024 Category: Neurology Source Type: research

Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia
AbstractThe stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson ’s disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING a...
Source: Acta Neuropathologica - March 13, 2024 Category: Neurology Source Type: research

Role of GBA variants in Lewy body disease neuropathology
AbstractRare and commonGBA variants are risk factors for both Parkinson ’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to whichGBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rareGBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putam...
Source: Acta Neuropathologica - March 12, 2024 Category: Neurology Source Type: research

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons
In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate t hat the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the “ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein” (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 12, 2024 Category: Neurology Source Type: research

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy
AbstractSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need ...
Source: Acta Neuropathologica - March 12, 2024 Category: Neurology Source Type: research

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson ’s disease
AbstractParkinson ’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50  years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples...
Source: Acta Neuropathologica - March 11, 2024 Category: Neurology Source Type: research

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study
AbstractSpinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and dis...
Source: Acta Neuropathologica - March 9, 2024 Category: Neurology Source Type: research

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS
AbstractTDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped humanpost-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection ofStathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical...
Source: Acta Neuropathologica - March 5, 2024 Category: Neurology Source Type: research

Methylation class oligosarcoma, IDH-mutant could exhibit astrocytoma-like molecular features
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 5, 2024 Category: Neurology Source Type: research