Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy
AbstractParkinson ’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s d...
Source: Acta Neuropathologica - June 6, 2019 Category: Neurology Source Type: research

An update on the CNS manifestations of neurofibromatosis type 2
AbstractNeurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in theNF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neu...
Source: Acta Neuropathologica - June 4, 2019 Category: Neurology Source Type: research

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players
AbstractChronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugb...
Source: Acta Neuropathologica - June 1, 2019 Category: Neurology Source Type: research

Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model
AbstractParkinson ’s disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) ex pressing human, aggregation-prone truncated 1–120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is assoc...
Source: Acta Neuropathologica - May 31, 2019 Category: Neurology Source Type: research

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation
AbstractGranulovacuolar degeneration (GVD) is usually found in Alzheimer ’s disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9;N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9;N = 46), a...
Source: Acta Neuropathologica - May 29, 2019 Category: Neurology Source Type: research

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer ’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
AbstractThe genetic variant rs72824905-G (minor allele) in thePLCG2 gene was previously associated with a reduced Alzheimer ’s disease risk (AD). The role ofPLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (...
Source: Acta Neuropathologica - May 27, 2019 Category: Neurology Source Type: research

ALK-positive histiocytosis with KIF5B - ALK fusion in the central nervous system
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 22, 2019 Category: Neurology Source Type: research

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes
AbstractIn 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4  MB subtypes...
Source: Acta Neuropathologica - May 10, 2019 Category: Neurology Source Type: research

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma
AbstractDNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1 –3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 m eningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylati...
Source: Acta Neuropathologica - May 8, 2019 Category: Neurology Source Type: research

Lack of H3K27 trimethylation is associated with 1p/19q codeletion in diffuse gliomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr 348 phosphorylation
In conclusion, our data support the idea that BIN1 modulates the AD risk through an intrica te regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

Revisiting the utility of TDP-43 immunoreactive (TDP-43-ir) pathology to classify FTLD-TDP subtypes
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

RhoA regulates translation of the Nogo-A decoy SPARC in white matter-invading glioblastomas
This study demonstrates that the prevalent activation of AKT in gliomas increases the ER protein-folding capacity and enables tumor cells to utilize a side effect of RhoA activation: the perturbation of the IRE1 α-mediated decay of SPARC mRNA. Once translation is initiated, glioblastoma cells rapidly secrete SPARC to block Nogo-A from inhibiting migration via RhoA. By advanced ultramicroscopy for studying single-cell invasion in whole, undissected mouse brains, we show that gliomas require SPARC for invadi ng into white matter structures. SPARC depletion reduces tumor dissemination that significantly prolongs surviva...
Source: Acta Neuropathologica - May 6, 2019 Category: Neurology Source Type: research

Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis
AbstractThe limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35 –55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in t...
Source: Acta Neuropathologica - April 27, 2019 Category: Neurology Source Type: research

Molecular progression of SHH-activated medulloblastomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 27, 2019 Category: Neurology Source Type: research

Endogenous oligodendroglial alpha-synuclein and TPPP/p25 α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models
AbstractMultiple system atrophy (MSA) is characterized by the presence of distinctive glial cytoplasmic inclusions (GCIs) within oligodendrocytes that contain the neuronal protein alpha-synuclein (aSyn) and the oligodendroglia-specific phosphoprotein TPPP/p25 α. However, the role of oligodendroglial aSyn and p25α in the formation of aSyn-rich GCIs remains unclear. To address this conundrum, we have applied human aSyn (haSyn) pre-formed fibrils (PFFs) to rat wild-type (WT)-, haSyn-, or p25α-overexpressing oligodendroglial cells and to primary different iated oligodendrocytes derived from WT, knockout (KO)-...
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling
AbstractSchwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. The data highlight for the first time that SC migrate preferentially along blood vessels in perivascular extracellular matrix (ECM), avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin signaling. Indeed, EphrinB3, enriched in myelin, interacts...
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Correction to: The origin, fate, and contribution of macrophages to spinal cord injury pathology
The original version of the article contains a labeling error in Fig.  2. The boxed molecular description of pro-inflammatory and anti-inflammatory macrophages were switched. Ly6CHi, Cx3Cr1Lo, Ccr2Hi should have been associated with pro-inflammatory macrophages on the left, and Ly6CLo, Cx3Cr1Hi, Ccr2Lo should have been associated with anti-inflammatory macrophages on the right. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer ’s disease
AbstractAlzheimer ’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activatio n is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucle...
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

Selective vulnerability in α-synucleinopathies
In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the “death by a thousand cuts” profile of α-synucleinopath ies. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

Detection of AD-specific four repeat tau with deamidated asparagine residue 279-specific fraction purified from 4R tau polyclonal antibody
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

The new genetic landscape of Alzheimer ’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?
AbstractA strong genetic predisposition (60 –80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approa...
Source: Acta Neuropathologica - April 13, 2019 Category: Neurology Source Type: research

Neurotoxicity of polychlorinated biphenyls and related organohalogens
AbstractHalogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many “legacy” compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcom es have also been noted. Here, we review human studies of pren...
Source: Acta Neuropathologica - April 11, 2019 Category: Neurology Source Type: research

An update on the central nervous system manifestations of tuberous sclerosis complex
AbstractThe autosomal dominant disorder tuberous sclerosis complex (TSC) is characterized by an array of manifestations both within and outside of the central nervous system (CNS), including hamartomas and other malformations. TSC is caused by mutations in theTSC1 orTSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Study of TSC has shed light on the critical role of the mTOR pathway in neurodevelopment. This update reviews the genetic basis of TSC, its cardinal phenotypic CNS features, and recent developments in the field of TSC and other mTOR-altered disorders. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 11, 2019 Category: Neurology Source Type: research

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and oα-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked oα-syn uptake. In cellular and trans genic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with α-syn accumulation. Notably, we could also demonstrate a direct interaction between α-syn...
Source: Acta Neuropathologica - April 11, 2019 Category: Neurology Source Type: research

Correction to: H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo
The original article can be found online. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 11, 2019 Category: Neurology Source Type: research

Neuroinflammation, the thread connecting neurological disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 9, 2019 Category: Neurology Source Type: research

An update on the central nervous system manifestations of neurofibromatosis type 1
AbstractNeurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder that presents with variable phenotypes as a result of mutations in the neurofibromatosis type 1 (NF1) gene and subsequently, abnormal function of the protein product, neurofibromin. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic disease. The mechanisms underlying the varied manifestations of NF1 are incompletely understood, but the loss of functional neurofibromin, resulting in sustained activation of the oncoprotein RAS, is responsible for tumorigenesis throu...
Source: Acta Neuropathologica - April 8, 2019 Category: Neurology Source Type: research

Severe bornavirus-encephalitis presenting as Guillain –Barré-syndrome
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 5, 2019 Category: Neurology Source Type: research

An update on the central nervous system manifestations of DICER1 syndrome
AbstractDICER1 syndrome is a rare tumor predisposition syndrome with manifestations that predominantly affect children and young adults. The syndrome is typically caused by heterozygous germline loss-of-functionDICER1 alterations accompanied on the other allele by somatic missense mutations occurring at one of a few mutation hotspots within the sequence encoding the RNase IIIb  domain.DICER1 encodes a member of the microRNA biogenesis machinery. The syndrome spectrum is highly pleiotropic and features a unique constellation of benign and malignant neoplastic and dysplastic lesions. Pleuropulmonary blastoma (PPB), the ...
Source: Acta Neuropathologica - April 5, 2019 Category: Neurology Source Type: research

Evaluation of CD33 as a genetic risk factor for Alzheimer ’s disease
AbstractIn 2011, genome-wide association studies implicated a polymorphism nearCD33 as a genetic risk factor for Alzheimer ’s disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found thatCD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying theCD33 genetic association with Alzheimer ’s disease. The allele that protects from Alzheimer’s disease acts predominately to increase aCD33 isoform lacking exon 2 at the expense of the prototypic, full-l...
Source: Acta Neuropathologica - April 4, 2019 Category: Neurology Source Type: research

Two molecularly distinct atypical teratoid/rhabdoid tumors (or tumor components) occurring in an infant with rhabdoid tumor predisposition syndrome 1
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 3, 2019 Category: Neurology Source Type: research

ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD
AbstractThe hexanucleotide repeat expansion GGGGCC (G4C2)n in theC9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for adenosine (A) to inosine (I) editing of double-stranded RNA, and its function has been shown t...
Source: Acta Neuropathologica - April 3, 2019 Category: Neurology Source Type: research

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
AbstractAmyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS ’ tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytop...
Source: Acta Neuropathologica - April 1, 2019 Category: Neurology Source Type: research

The origin, fate, and contribution of macrophages to spinal cord injury pathology
AbstractVirtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. In this review, we also consider the possibility that different macroph...
Source: Acta Neuropathologica - March 30, 2019 Category: Neurology Source Type: research

LRRK2 modifies α-syn pathology and spread in mouse models and human neurons
AbstractProgressive aggregation of the protein alpha-synuclein ( α-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson’s disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of th e disease. Thus, it is therapeutically pertinent to identify modifiers of α-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in st...
Source: Acta Neuropathologica - March 29, 2019 Category: Neurology Source Type: research

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus –Merzbacher disease
AbstractPelizaeus –Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood–brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not le ad to a major advancement of hypomyelination, potentially because the intact blood–brain barrier precludes its entry into the CNS. We therefore turned to a PMD mouse model with preserved blood–brain barrier integrity and show that a high-fat/low-carbohydrate ketogenic diet restored oligoden...
Source: Acta Neuropathologica - March 27, 2019 Category: Neurology Source Type: research

An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 27, 2019 Category: Neurology Source Type: research

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data
AbstractMassive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases  as compared to controls:TREM2,SORL1, andABCA7.SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (A β) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. CommonSORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rareSORL1 c...
Source: Acta Neuropathologica - March 25, 2019 Category: Neurology Source Type: research

The role of ABCA7 in Alzheimer ’s disease: evidence from genomics, transcriptomics and methylomics
In conclusion, human-based –omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions onABCA7 expression can serve as a valuable therapeutic target for AD. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 22, 2019 Category: Neurology Source Type: research

Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity
AbstractBoth α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson’s disease (PD). Although studies suggest that αSyn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which αSyn and mitochondrial prote ins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Here, we show that the protein le...
Source: Acta Neuropathologica - March 15, 2019 Category: Neurology Source Type: research

ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response
AbstractMutations in coiled-coil-helix –coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice har boring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 spe...
Source: Acta Neuropathologica - March 14, 2019 Category: Neurology Source Type: research

Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 14, 2019 Category: Neurology Source Type: research

Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10 S59L/+ mouse
We reported patients, carrying the p.Ser59Leu heterozygous mutation inCHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Rapidly, our group and others reportedCHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia-ALS and other neurodegenerative diseases. Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family. Before 14  months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enh...
Source: Acta Neuropathologica - March 14, 2019 Category: Neurology Source Type: research

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability
In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4  Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6).DPP6 resequencing identified significantly more rare variants —nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD,p value  = 0.03, OR = 2.21 95% CI 1.05–4.82) and frontotemporal dementia (...
Source: Acta Neuropathologica - March 14, 2019 Category: Neurology Source Type: research

The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
AbstractMutations insuperoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approach...
Source: Acta Neuropathologica - March 12, 2019 Category: Neurology Source Type: research

cIMPACT-NOW update 4: diffuse gliomas characterized by MYB , MYBL1 , or FGFR1 alterations or BRAF V600E mutation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 8, 2019 Category: Neurology Source Type: research

SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 8, 2019 Category: Neurology Source Type: research

The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis
AbstractNeuroinflammation is the coordinated response of the central nervous system (CNS) to threats to its integrity posed by a variety of conditions, including autoimmunity, pathogens and trauma. Activated astrocytes, in concert with other cellular elements of the CNS and immune system, are important players in the modulation of the neuroinflammatory response. During neurological disease, they produce and respond to cellular signals that often lead to dichotomous processes, which can promote further damage or contribute to repair. This occurs also in multiple sclerosis (MS), where astrocytes are now recognized as key com...
Source: Acta Neuropathologica - March 7, 2019 Category: Neurology Source Type: research

Mission not yet completed: on the ups and downs of being the editor of ANP
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 5, 2019 Category: Neurology Source Type: research