The variance in phosphorylated, insoluble ⍺-synuclein in humans, rats, and mice is not mainly driven by biological sex
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 11, 2023 Category: Neurology Source Type: research
TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models
AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that prima...
Source: Acta Neuropathologica - August 9, 2023 Category: Neurology Source Type: research
Inflammation and the pathological progression of Alzheimer ’s disease are associated with low circulating choline levels
AbstractDeficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer’s disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impair ment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderat...
Source: Acta Neuropathologica - August 7, 2023 Category: Neurology Source Type: research
Decreased dystrophin expression and elevated dystrophin-targeting miRNAs in anti-HMGCR immune-mediated necrotizing myopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 5, 2023 Category: Neurology Source Type: research
Correction to: Intraneuronal aggregation of the β‑CTF fragment of APP (C99) induces Aβ‑independent lysosomal-autophagic pathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 4, 2023 Category: Neurology Source Type: research
A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4
AbstractMalignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34...
Source: Acta Neuropathologica - July 31, 2023 Category: Neurology Source Type: research
DNA-methylation subgroups carry no prognostic significance in ATRT-SHH patients in clinical trial cohorts
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 31, 2023 Category: Neurology Source Type: research
AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model
AbstractHereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants inAMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncatingAMFR variants, resulting in a cohort of 20 in...
Source: Acta Neuropathologica - July 27, 2023 Category: Neurology Source Type: research
Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium ‘leak’ in tremor pathophysiology
In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correla ted with loss of PCs and climbing fiber-PC synapses in ET. This ‘leaky’ RyR1 signature was not seen in control or Parkinson’s disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 po...
Source: Acta Neuropathologica - July 27, 2023 Category: Neurology Source Type: research
Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis
In this study, we provide evidence for a central role of LRRK2 in gut inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimenta l colitis based on chronic dextran sulphate sodium (DSS) administration. Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental colitis model. Furthermore, partial ph armacological inhibition of LRRK2 kinase activity also reduced the colitis phenot...
Source: Acta Neuropathologica - July 27, 2023 Category: Neurology Source Type: research
From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions
In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity. We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n = 9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using...
Source: Acta Neuropathologica - July 27, 2023 Category: Neurology Source Type: research
Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas
In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24–217) and 2 insertions/deletions (range 0–22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79–53.49%) of SNVs mapping to i ts target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV− PCNSL. Instead, EBV+ P...
Source: Acta Neuropathologica - July 26, 2023 Category: Neurology Source Type: research
Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS
AbstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from humanpost-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progre...
Source: Acta Neuropathologica - July 24, 2023 Category: Neurology Source Type: research
