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1.
Artículo en Inglés | MEDLINE | ID: mdl-38916909

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important.

2.
Prion ; 18(1): 40-53, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38627365

RESUMEN

Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Enfermedades Neurodegenerativas , Enfermedades por Prión , Priones , Humanos , Proteínas Priónicas , Proteínas PrPSc/metabolismo , Adhesión en Parafina , Enfermedades por Prión/diagnóstico , Enfermedades por Prión/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Priones/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Endopeptidasa K , Anticuerpos , Formaldehído
3.
Neuropathology ; 44(1): 31-40, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37340992

RESUMEN

Neuronal intranuclear inclusions (NIIs) are common key structures in polyglutamine (polyQ) diseases such as Huntington disease (HD), spinocerebellar ataxia type 1 (SCA1), and SCA3. Marinesco bodies (MBs) of dopaminergic neurons in the substantia nigra are also intranuclear structures and are frequently seen in normal elderly people. Ribosomal dysfunction is closely related to two differential processes; therefore, we aimed to identify the pathological characteristics of ribosomal protein SA (RPSA), a ribosomal protein, in both states. To this end, we evaluated the autopsy findings in four patients with HD, two SCA3, and five normal elderly cases (NCs). Immunohistochemical studies demonstrated that both NIIs and MBs contain RPSA. In polyQ diseases, RPSA was co-localized with polyQ aggregations, and 3D-reconstructed images revealed their mosaic-like distribution. Assessments of the organization of RPSA and p62 in NIIs showed that RPSA was more localized toward the center than p62 and that this unique organization was more evident in the MBs. Immunoblotting of the temporal cortices revealed that the nuclear fraction of HD patients contained more RPSA than that of NCs. In conclusion, our study revealed that RPSA is a common component of both NIIs and MBs, indicating that a similar mechanism contributes to the formation of polyQ NIIs and MBs.


Asunto(s)
Encéfalo , Cuerpos de Inclusión Intranucleares , Anciano , Humanos , Encéfalo/patología , Cuerpos de Inclusión Intranucleares/metabolismo , Péptidos/metabolismo , Proteínas Ribosómicas/metabolismo
4.
Brain Pathol ; 34(2): e13191, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-37586842

RESUMEN

FUS mutations are one of the major mutations in familial amyotrophic lateral sclerosis (ALS). The pathological hallmark is FUS-positive neuronal cytoplasmic inclusions (FUS-NCI), known as FUS proteinopathy. Human myxovirus resistance protein 1 (MxA) is an IFN-induced dynamin-like GTPase that acts as antiviral factor. In this study, we examined the expression of MxA in neurons bearing FUS-NCI. We performed immunohistochemistry for FUS and MxA to examine the expression of MxA in two autopsy cases with different FUS gene mutations localized at the nuclear localization signal site (Case 1, H517P; Case 2, R521C). MxA. Most neurons bearing FUS-NCI have increased cytoplasmic MxA expression. Increased cytoplasmic MxA showed several distribution patterns in relation to FUS-NCIs such as the following: colocalization with NCI, distribution more widely than NCI, and different distribution peaks from NCI. Our results suggested that antiviral signaling IFNs are involved upstream in the formation of FUS-NCI in ALS-FUS patients.


Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/patología , Antivirales/metabolismo , Mutación , Neuronas/patología , Proteína FUS de Unión a ARN/genética
5.
J Neuropathol Exp Neurol ; 82(3): 231-241, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36592411

RESUMEN

Fused in sarcoma (FUS), coded by FUS, is a heterogeneous nuclear ribonucleoprotein (hnRNP). FUS mutations are among the major mutations in familial amyotrophic lateral sclerosis (ALS-FUS: ALS6). The pathological hallmarks of ALS-FUS are FUS-positive neuronal cytoplasmic inclusions (NCI). We examined various hnRNPs in FUS NCIs in the hippocampus in ALS-FUS cases with different FUS mutations (Case 1, H517P; Case 2, R521C). We also examined TDP43-positive NCIs in sporadic ALS hippocampi. Immunohistochemistry was performed using primary antibodies against FUS, p-TDP43, TDP43, hnRNPA1, hnRNPD, PCBP1, PCBP2, and p62. Numerous FUS inclusions were found in the hippocampal granule and pyramidal cell layers. Double immunofluorescence revealed colocalization of FUS and p-TDP43, and FUS and PCBP2 (p-TDP43/FUS: 64.3%, PCBP2/FUS: 23.9%). Colocalization of FUS and PCBP1, however, was rare (PCBP1/FUS: 7.6%). In the hippocampi of patients with sporadic ALS, no colocalization was observed between TDP43-positive inclusions and other hnRNPs. This is the first study to show that FUS inclusions colocalize with other hnRNPs, such as TDP43, PCBP2, and PCBP1. These findings suggest that in ALS-FUS, FUS inclusions are the initiators, followed by alterations of multiple other hnRNPs, resulting in impaired RNA metabolism.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína FUS de Unión a ARN , Humanos , Esclerosis Amiotrófica Lateral/patología , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Cuerpos de Inclusión/patología , Mutación/genética , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
6.
J Neuropathol Exp Neurol ; 82(1): 29-37, 2022 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-36331500

RESUMEN

Myotonic dystrophy type 1 (DM1) is an inherited autosomal-dominant condition that induces altered splicing of transcripts, including MAPT, leading to a distinctive abnormal deposition of tau protein in the CNS. We characterized the tau isoforms of abnormal depositions in the brains of 4 patients with classic DM1 by immunohistochemistry using isoform-specific antibodies. All patients, including those of presenile age, showed numerous neurofibrillary tangles (NFTs) of both 3-repeat and 4-repeat tau in the limbic area and mild involvement in the cerebral cortex. Amyloid-ß deposition was only seen in 1 senile case while cortical tauopathy in all other cases was consistent with primary age-related tauopathy (PART). In the putamen and globus pallidus, only a few tau deposits were observed. Tau deposits in the brainstem frequently showed a DM1-specific pattern with 3-repeat tau dominant NFTs. Additionally, tau-positive astrocytes morphologically similar to tufted astrocytes and astrocytic plaques were occasionally observed in the brainstem; however, they were predominantly composed of 3-repeat tau. Thus, the classic DM1 showed both early onset of PART-like pathology in the limbic areas as a progeroid syndrome of DM1 and an abnormal splicing event in the brainstem leading to 3-repeat tau dominant accumulation with both neuronal and astrocytic involvement.


Asunto(s)
Tronco Encefálico , Hipocampo , Distrofia Miotónica , Tauopatías , Proteínas tau , Humanos , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Hipocampo/metabolismo , Hipocampo/patología , Distrofia Miotónica/metabolismo , Distrofia Miotónica/patología , Ovillos Neurofibrilares/patología , Isoformas de Proteínas/metabolismo , Proteínas tau/metabolismo , Tauopatías/patología
7.
J Neuropathol Exp Neurol ; 82(1): 38-48, 2022 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-36331509

RESUMEN

GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Proteínas de la Membrana , Microglía , Receptores Purinérgicos P2Y12 , Humanos , Síndrome de Creutzfeldt-Jakob/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Microglía/metabolismo , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo
8.
Sci Rep ; 12(1): 15289, 2022 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-36088465

RESUMEN

Prion disease is an infectious and fatal neurodegenerative disease. Human prion disease autopsy studies have revealed abnormal prion protein (PrPSc) deposits in the central nervous system and systemic organs. In deer, chronic wasting disease has also become a global problem, with PrPSc in saliva and feces. Therefore, understanding normal cellular prion proteins (PrPc) characteristics in human systemic organs is important since they could be a PrPSc source. This study used western blotting and immunohistochemistry to investigate endocrine and exocrine tissues, such as the human pituitary, adrenal, submandibular glands and the pancreas. All tissues had 30-40 kDa PrP signals, which is a slightly higher molecular weight than normal brain tissue. Most cytoplasmic PrP-positive adenohypophyseal cells were immunopositive for nuclear pituitary-specific positive transcription factor 1. The adrenal medulla and islet cells of the pancreas were PrP-positive and colocalized with chromogranin A. The duct epithelium in the submandibular gland and pancreas were immunopositive for PrP. This study reports the characteristic molecular properties and detailed tissue localization of PrPc in endocrine and exocrine tissues, which is important for infection control and diagnosis.


Asunto(s)
Proteínas Priónicas/química , Animales , Ciervos , Humanos , Especificidad de Órganos , Enfermedades por Prión/metabolismo
9.
J Neuropathol Exp Neurol ; 81(11): 900-909, 2022 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-36063412

RESUMEN

The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of <2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Priones , Humanos , Síndrome de Creutzfeldt-Jakob/patología , Proteínas Priónicas/metabolismo , Proteínas PrPSc/metabolismo , Progresión de la Enfermedad , Hipocampo/patología , Encéfalo/patología
10.
J Neuropathol Exp Neurol ; 81(2): 106-116, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-34875089

RESUMEN

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.


Asunto(s)
Enfermedad de Alzheimer/patología , Astrocitos/patología , Encéfalo/patología , Nervio Olfatorio/patología , Anciano , Anciano de 80 o más Años , Envejecimiento , Pueblo Asiatico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
11.
Brain Pathol ; 32(1): e13014, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34390072

RESUMEN

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. ß amyloid (Aß) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aß phase score (A2-3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V-VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Humanos , Ovillos Neurofibrilares/metabolismo , Placa Amiloide/patología , Prealbúmina/metabolismo
12.
Front Immunol ; 12: 670131, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34267749

RESUMEN

Targeting the unique glioma immune microenvironment is a promising approach in developing breakthrough immunotherapy treatments. However, recent advances in immunotherapy, including the development of immune checkpoint inhibitors, have not improved the outcomes of patients with glioma. A way of monitoring biological activity of immune cells in neural tissues affected by glioma should be developed to address this lack of sensitivity to immunotherapy. Thus, in this study, we sought to examine the feasibility of non-invasive monitoring of glioma-associated microglia/macrophages (GAM) by utilizing our previously developed induced microglia-like (iMG) cells. Primary microglia (pMG) were isolated from surgically obtained brain tissues of 22 patients with neurological diseases. iMG cells were produced from monocytes extracted from the patients' peripheral blood. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant correlation of the expression levels of representative markers for M1 and M2 microglia phenotypes between pMG and the corresponding iMG cells in each patient (Spearman's correlation coefficient = 0.5225, P <0.0001). Synchronous upregulation of CD206 expression levels was observed in most patients with glioma (6/9, 66.7%) and almost all patients with glioblastoma (4/5, 80%). Therefore, iMG cells can be used as a minimally invasive tool for monitoring the disease-related immunological state of GAM in various brain diseases, including glioma. CD206 upregulation detected in iMG cells can be used as a surrogate biomarker of glioma.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/sangre , Glioma/sangre , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Proteínas de Unión al Calcio/metabolismo , Células Cultivadas , Estudios de Factibilidad , Femenino , Glioma/inmunología , Glioma/patología , Glioma/cirugía , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Microfilamentos/metabolismo , Microglía/inmunología , Microglía/patología , Monitorización Inmunológica , Fenotipo , Pronóstico , Receptores Inmunológicos/genética , Microambiente Tumoral
13.
Neuropathology ; 41(4): 253-265, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34031922

RESUMEN

Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11.


Asunto(s)
Proteínas de Unión al ADN , Paraplejía Espástica Hereditaria , Humanos , Lisosomas , Mutación , Proteínas , Proteinopatías TDP-43 , Activación Transcripcional
14.
Neuropathology ; 41(2): 146-151, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33404144

RESUMEN

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease, characterized by the progressive ossification of skeletal muscles, fascia, tendons, and ligaments. In most cases, the great toes of patients show symmetrical congenital malformations. The causative gene for FOP has been identified as the activin A receptor, type 1 (ACVR1) gene (ACVR1). The ACVR1 R206H mutation is the most common mutation among FOP patients, and the ACVR1 G356D mutation has been identified as a rare mutation in a Japanese FOP patient with slow progression. In addition to musculoskeletal abnormalities, a series of autopsy studies described one FOP case, without genetic testing to identify ACVR1 mutation, showing nodular heterotopia at the edge of the fourth ventricle. Here, we report the general autopsy findings for a 75-year-old man with FOP, caused by the ACVR1 G356D mutation, including the precise examination of brainstem lesions. Postmortem examination revealed unique symmetrical glial hyperplasia of the pons and medulla oblongata. Microscopically, lesions of the pons involving residual neurons and lesions of the medulla oblongata consisted of subependymal cells. Immunohistochemical analysis of these lesions revealed developmental anomalies, with different cellular components. In this report, for the first time, we present the neuropathological description of a patient with genetically confirmed FOP and symmetrical glial hyperplasia of the pons and medulla oblongata. The presented pathological findings, in conjunction with previous reports implying that the glial hyperplasia of the brainstem is common in FOP, suggest that ACVR1 may play an unclarified developmental role in the human brainstem.


Asunto(s)
Tronco Encefálico/patología , Hiperplasia/patología , Miositis Osificante/patología , Neuroglía/patología , Anciano , Pruebas Genéticas/métodos , Humanos , Hiperplasia/genética , Masculino , Mutación/genética , Miositis Osificante/diagnóstico , Miositis Osificante/genética
15.
J Neuropathol Exp Neurol ; 80(3): 220-228, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33313661

RESUMEN

Various heterogeneous nuclear ribonucleoproteins (hnRNPs) are deposited in pathological inclusions of amyotrophic lateral sclerosis (ALS) and related diseases, such as frontotemporal lobar degeneration (FTLD). Recently, poly (rC)-binding protein 2 (PCBP2, hnRNP-E2), a member of the hnRNP family, was reported to be colocalized with transactivation-responsive DNA-binding protein 43 kDa (TDP-43)-immunopositive inclusions in cases of FTLD-TDP. Here, we used immunohistochemical methods to investigate PCBP1 and PCBP2 expression in the spinal cords of sporadic ALS patients, with special reference to TDP-43-positive inclusions. Thirty autopsy cases of sporadic ALS were examined by immunohistochemistry using antibodies against PCBP1, PCBP2, sequestosome 1 (p62), and TDP-43. In control subjects without neurological disorders, neurons predominantly expressed PCBP2, rather than PCBP1, in their cytoplasm and nuclei. Anterior horn cells of sporadic ALS patients often had various levels of PCBP2 expression, and motor neurons with skein-like inclusions often had reduced or lost cytoplasmic and nuclear PCBP2 staining. Notably, one case with FTLD-TDP subtype B pathology had marked colocalization of TDP-43 and PCBP2 in the cytoplasmic inclusions and dystrophic neurites of the cerebral cortex, hippocampus, and spinal cord. In conclusion, PCBP2 was reduced in anterior horn cells of sporadic ALS, but its occurrence in TDP-43 inclusions was a rare phenomenon.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/metabolismo , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Proteínas de Unión al ARN/metabolismo , Adolescente , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad
16.
J Neuropathol Exp Neurol ; 78(10): 961-970, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504683

RESUMEN

Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage.


Asunto(s)
Anexina A1/metabolismo , Astrocitos/metabolismo , Infarto Encefálico/metabolismo , Encéfalo/metabolismo , Microglía/metabolismo , Regulación hacia Arriba , Adulto , Anciano , Anciano de 80 o más Años , Acuaporina 4/metabolismo , Astrocitos/patología , Encéfalo/patología , Infarto Encefálico/patología , Transportador 1 de Aminoácidos Excitadores/metabolismo , Femenino , Humanos , Masculino , Microglía/patología , Persona de Mediana Edad , Adulto Joven
17.
J Neuropathol Exp Neurol ; 78(10): 922-929, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504701

RESUMEN

Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells.


Asunto(s)
Encéfalo/patología , Hipófisis/patología , Proteínas PrPSc/metabolismo , Enfermedades por Prión/patología , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipófisis/metabolismo , Enfermedades por Prión/metabolismo , Proteómica
18.
Alzheimers Dement (Amst) ; 11: 415-423, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31206007

RESUMEN

INTRODUCTION: We have conducted the pathological cohort study of autopsied cases of Hisayama residents to reveal a recent trend of dementia-related pathology. We noticed a trend of putaminal involvement of Alzheimer's disease (AD) with parkinsonism. Then, we investigated the accurate prevalence of neurological diseases with putaminal AD pathology in the general population. METHODS: We examined a series of 291 autopsies in the Hisayama study and performed image analysis of immunohistochemistry for microtubule-associated protein tau (MAPT) and amyloid ß. RESULTS: Approximately 65.6% and 36.1% of cases showed putaminal MAPT and amyloid deposits, respectively. Diffuse deposits of them were mainly found in the AD cases. Putaminal MAPT was highly associated with AD-related pathological criteria. Four of 22 cases with severe putaminal MAPT deposition were documented as having developed parkinsonism. DISCUSSION: Severe MAPT accumulation in the basal ganglia was closely related to the development of AD pathology and could occur most frequently in AD cases without comorbidities.

19.
Neuropathology ; 38(6): 583-590, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30215870

RESUMEN

Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology.


Asunto(s)
Encéfalo/patología , Complejo Dinactina/metabolismo , Cuerpos de Lewy/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/patología
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