| 1. |
- Andersson, Ulrika, et al.
(författare)
-
Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas
- 2004
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 108:2, s. 135-142
-
Tidskriftsartikel (refereegranskat)abstract
- Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.
|
|
| 2. |
- Ekhtiari Bidhendi, Elaheh, et al.
(författare)
-
Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
- 2018
-
Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 136:6, s. 939-953
-
Tidskriftsartikel (refereegranskat)abstract
- Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.
|
|
| 3. |
- Forsberg, Karin, et al.
(författare)
-
Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis
- 2011
-
Ingår i: Acta Neuropathologica. - : SpringerLink. - 0001-6322 .- 1432-0533. ; 121:5, s. 623-634
-
Tidskriftsartikel (refereegranskat)abstract
- The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.
|
|
| 4. |
- Forsberg, Karin, et al.
(författare)
-
Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation
- 2023
-
Ingår i: Acta Neuropathologica. - : Springer-Verlag New York. - 0001-6322 .- 1432-0533. ; 145:1, s. 13-28
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.
|
|
| 5. |
- Hu, XiaoLei, et al.
(författare)
-
Long-lasting neuronal apoptotic cell death in regions with severe ischemia after photothrombotic ring stroke in rats
- 2002
-
Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 104:5, s. 462-70
-
Tidskriftsartikel (refereegranskat)abstract
- Apoptotic and necrotic cell death may act in concert in focal cerebral ischemia. This study explored the temporal and spatial pattern of apoptosis and necrosis in a novel photothrombotic ring stroke model with or without spontaneous reperfusion. Adult male Wistar rats were subjected to a ring-shaped laser irradiation beam simultaneously with intravenous erythrosin B infusion. The presence and attributes of apoptosis and necrosis in the anatomically well-defined cortical region at risk and ring-lesion region were verified under light microscopy with TUNEL, Hoechst 33342, and hematoxylin and eosin staining. Cells exhibiting apoptotic morphology with chromatin condensation and apoptotic bodies and necrotic ghost appearance were observed. The occurrence of apoptosis and necrosis in the ischemic regions was confirmed by electron microscopy and gel electrophoresis, in which DNA isolated from the lesion area revealed both a ladder and a smear. Double staining with TUNEL and the cell markers NeuN, glial fibrillary acidic protein, and ED-1 revealed that the majority of apoptotic cells were of neuronal origin. Cells exhibiting pyknosis/eosinophilia, apoptosis, or ghost appearance were quantified by stereological means. In subregions with severe ischemia, the peak appearance of apoptotic cells started earlier, i.e., at 24 h, than the peak of necrotic cells, and the high concentration of the apoptotic cells remained as long as that of necrotic cells, i.e., until 72 h post-ischemia. The ratio of apoptotic to necrotic cells was approximately 1:2. Therefore, apoptosis may be an important contributor to neuronal cell death in brain regions with severely reduced blood flow after thrombo-embolic stroke.
|
|
| 6. |
- Jonasson, Jenni, et al.
(författare)
-
Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
- 2002
-
Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 104:1, s. 29-37
-
Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.
|
|
| 7. |
- Keskin, Isil, 1987-, et al.
(författare)
-
The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
- 2019
-
Ingår i: Acta Neuropathologica. - New York : Springer. - 0001-6322 .- 1432-0533. ; 138:1, s. 85-101
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in superoxide 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 approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.
|
|
| 8. |
- Wang, Chao, et al.
(författare)
-
The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
- 2014
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:4, s. 507-522
-
Tidskriftsartikel (refereegranskat)abstract
- Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.
|
|
