Abstract:
:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Blokhuis AM,Groen EJ,Koppers M,van den Berg LH,Pasterkamp RJdoi
10.1007/s00401-013-1125-6subject
Has Abstractpub_date
2013-06-01 00:00:00pages
777-94issue
6eissn
0001-6322issn
1432-0533journal_volume
125pub_type
杂志文章,评审abstract::Matrix metalloproteinases (MMPs) are endoproteases that have been implicated in the pathogenesis of inflammatory and vasculitic neuropathies. In systemic lupus erythematosus (SLE), a peripheral neuropathy is frequently seen that is thought to be caused by ischemic nerve damage due to vasculopathy and/or vasculitis of ...
journal_title:Acta neuropathologica
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abstract::The character of the silver positive reticulin network was analyzed with immunofluorescence and immunoperoxidase methods in an intra vitam diagnosed case of primary brain lymphoma. The network was shown to contain connective tissue proteins rich in hexose-sugars, such as type III collagen (classical "reticulin"), basa...
journal_title:Acta neuropathologica
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doi:10.1007/BF00690962
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abstract::Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generatio...
journal_title:Acta neuropathologica
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abstract::The ultrastructure of the nervous tissue in a benign ovarian teratoma is described. This tissue was organized into areas having both "meningeal" and "ependymal" surfaces, between which were found astrocytes, ependymal cells, neurones with synapses and microglia. These cells all had ultrastructural similarities to thei...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686623
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abstract::Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-011-0940-x
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abstract::The present investigation examined the morphological characteristics of epiplexus macrophages following a single intracisternal injection of the antigen, bacillus Calmette-Guerin (BCG). Three days following injection of BCG (0.5 - 4.0 X 10(8) viable microorganisms), mongrel dogs were perfused with buffered aldehydes. ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690545
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abstract::A simple and reproducible method for cryopreservation of brain tissue from patients with Alzheimer's disease is described. Fresh brain slices (1 cm thick) obtained less than 6 h postmortem are placed in sealed plastic bags, sandwiched between 0.3-cm-thick aluminium sheets, and frozen by placing the entire "sandwich" b...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294305
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abstract::In the nerve tissue with proliferating macroglia cells were observed a lowered oxygen consumption, an increased aerobic glycolysis and alanine formation and a higher alanine aminotransferase and glutamate dehydrogenase activity than in the control tissue in the homogenates and in the cell sap fraction. The substrate s...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00684665
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abstract::Using a four-step immunoperoxidase (PAP) method and the monoclonal antibody MAbA9-C6 (MAbA9-C6), which defines an epitope of the retinal S-antigen (S-Ag), we investigated the S-Ag immunoreactivity in human fetal, newborn, infantile and adult pineal glands and in 13 human pineal parenchymal tumors. S-Ag immunoreactivit...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688043
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abstract::Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubi...
journal_title:Acta neuropathologica
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更新日期:2012-08-01 00:00:00
abstract::Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer's disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-012-1065-6
更新日期:2013-02-01 00:00:00
abstract::Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-015-1406-3
更新日期:2015-05-01 00:00:00
abstract::We investigated the distribution of prion protein (PrP) in 14 German patients with sporadic Creutzfeldt-Jakob disease (CJD) and compared it with that observed in Japanese patients. Immunohistochemical study revealed diffuse gray matter stainings including synaptic structures in all cases. In addition, 4 patients showe...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294174
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abstract::A macrosomic male infant with multiple malformations survived for 4 days. His external dysplasias comprised macrocephalus, cheilopalatoschisis, auricular anomalies, and unilateral hexadactyl; his internal dysplasias included cysts of kidneys and pancreas, and a patent foramen ovale. The child had frequent generalized ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690449
更新日期:1980-01-01 00:00:00
abstract::A quantitative technique involving serial sectioning and semiautomatic morphometric analysis was used to assess the severity of the reduction in size of the major brain structures in cerebral hemispheres of children congenitally infected with HIV-1. Cerebral hemispheres from 12 children (18-48 months of age) who died ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050594
更新日期:1997-02-01 00:00:00
abstract::Considering the possibility of a paracellular route for edema resolution we studied the microvasculature of the subependymal and subcortical white matter in hydrocephalic rats. Normal adult rats were used as controls. After injection of kaolin suspension into the cisterna magna, the animals were killed at intervals of...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00695575
更新日期:1984-01-01 00:00:00
abstract::Oxidative stress has been implicated in the pathogenesis of a number of diseases including Alzheimer's disease (AD). The oxidative stress hypothesis of AD pathogenesis, in part, is based on beta-amyloid peptide (Abeta)-induced oxidative stress in both in vitro and in vivo studies. Oxidative modification of the protein...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-009-0517-0
更新日期:2009-07-01 00:00:00
abstract::The distribution of apolipoprotein E (ApoE) was studied in the brain tissue of cases of the amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam, locally known as lytico bodig disease (LB), and compared with cases of Alzheimer's disease (AD) and normal brain tissue. In both LB and AD, strong ApoE immuno...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050533
更新日期:1996-10-01 00:00:00
abstract::Marinesco-Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident cha...
journal_title:Acta neuropathologica
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更新日期:2014-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/BF00687050
更新日期:1986-01-01 00:00:00
abstract::Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PS...
journal_title:Acta neuropathologica
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abstract::A 1-year-old male chinchilla with a 2-week history of conjunctivitis suffered subsequently from neurological signs comprising seizures, disorientation, recumbency and apathy. After 3 weeks of progressive central nervous disease the animal was killed in view of the poor prognosis. A non-suppurative meningitis and polio...
journal_title:Acta neuropathologica
pub_type: 杂志文章
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更新日期:2002-12-01 00:00:00
abstract::The nuclei for the nerves of a dorsal (m. splenius) and a ventral (m. longus capitis) neck muscle of the rat were retrogradely labeled by applying horseradish peroxidase (HRP) to the respective cut muscle nerves. Motoneurons of both muscles were analyzed for their localization, diameter of perikarya, and area of dendr...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690368
更新日期:1981-01-01 00:00:00
abstract::Investigations of the existence and distribution of muscle spindles and tendon organs in the human voluntary anal sphincter muscle in 53 cases of autopsy material from both female and male persons (age: 27th week of gestation to 81 years) brought forward the following results: Similar to animals, muscle spindles are f...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691860
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abstract::Experimental neuropathy, characterized by endoneurial edema and demyelination, was induced by inoculating rabbits with a combination of Freund's complete adjuvant (FCA), gangliosides, lecithin and cholesterol. A less severe demyelinating neuropathy could be induced by treatment with FCA alone but no significant change...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00695496
更新日期:1987-01-01 00:00:00
abstract::Mineralization in the wall of central nervous system blood vessels is sporadically encountered in aged horses and cattle as in man, generally as an age-related change. This phenomenon has not to date been located in the meninges in dogs or cats. The present study reports a retrospective histological examination of 50 ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-002-0641-6
更新日期:2003-03-01 00:00:00
abstract::In Alzheimer's disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence ...
journal_title:Acta neuropathologica
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更新日期:2018-11-01 00:00:00
abstract::Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate ...
journal_title:Acta neuropathologica
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更新日期:2012-09-01 00:00:00
abstract::To clarify the significance of the constituents of canine senile plaques (SPs) or cerebrovascular amyloid deposits, paraffin and cryostat sections of canine brains were examined by immunohistochemistry using antibodies against cathepsin B (CB), cathepsin D (CD), cystatin C (CC), alpha-1-antichymotrypsin (ACT), heat sh...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050615
更新日期:1997-03-01 00:00:00
abstract::An in vivo method for positively staining dead neurons was developed and compared with an in vitro staining method using acid fuchsin. Neurons previously killed by intracerebral injections of kainic acid were selectively stained by trypan blue within 15 min of its injection in vivo into the central nervous system of r...
journal_title:Acta neuropathologica
pub_type: 杂志文章
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