SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration
AbstractGEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations inGEMIN5 lead to a neurodevelopmental syndrome among patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN complex protein expression and assembly. Currently, molecular determinants of GEMIN5-mediated disease have yet to be explored. Here, we identified SMN as a genetic suppressor of GEMIN5-mediated neurodegeneration in vivo. We discovered that an increase in SMN expression by either SMN gene therapy replace...
Source: Acta Neuropathologica - June 27, 2023 Category: Neurology Source Type: research
A T-cell antigen atlas for meningioma: novel options for immunotherapy
AbstractMeningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood –brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the natu...
Source: Acta Neuropathologica - June 27, 2023 Category: Neurology Source Type: research
SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration
AbstractGEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations inGEMIN5 lead to a neurodevelopmental syndrome among patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN complex protein expression and assembly. Currently, molecular determinants of GEMIN5-mediated disease have yet to be explored. Here, we identified SMN as a genetic suppressor of GEMIN5-mediated neurodegeneration in vivo. We discovered that an increase in SMN expression by either SMN gene therapy replace...
Source: Acta Neuropathologica - June 27, 2023 Category: Neurology Source Type: research
A T-cell antigen atlas for meningioma: novel options for immunotherapy
AbstractMeningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood –brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the natu...
Source: Acta Neuropathologica - June 27, 2023 Category: Neurology Source Type: research
Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
AbstractMicrotubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducingMAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial...
Source: Acta Neuropathologica - June 24, 2023 Category: Neurology Source Type: research
Mutation ∆K281 in MAPT causes Pick’s disease
AbstractTwo siblings with deletion mutation ∆K281 inMAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas–Braak silver. They were not l abelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of t...
Source: Acta Neuropathologica - June 23, 2023 Category: Neurology Source Type: research
Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes
AbstractParkinson ´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have ide ntified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed t o elucidat...
Source: Acta Neuropathologica - June 22, 2023 Category: Neurology Source Type: research
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
AbstractInsoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer ’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sark osyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of b...
Source: Acta Neuropathologica - June 21, 2023 Category: Neurology Source Type: research
Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology
AbstractSerum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct molecular mechanisms: complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether multi-pathogenicity is mediated by individual or multiple autoantibody clones. Using an unbiased B cell culture screening approach, we generated a library of 11 human-derived AChR-specific recombinant monoclonal autoantibodies (mAb) and assessed their binding properties and pathogenic profiles using specialized cell-based assays. Fi...
Source: Acta Neuropathologica - June 21, 2023 Category: Neurology Source Type: research
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
AbstractInsoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer ’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sark osyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of b...
Source: Acta Neuropathologica - June 21, 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 - June 19, 2023 Category: Neurology Source Type: research
