Pub Date : 2005-06-01DOI: 10.1097/01.jnen.0000166798.69322.4e
K. McFadden, R. Hamilton, S. Insalaco, L. Lavine, M. Al-Mateen, Guoji Wang, C. Wiley
Neuronal intranuclear inclusion disease (NIID) is a rare and heterogeneous group of slowly progressive neurodegenerative disorders characterized by the widespread presence of eosinophilic neuronal intranuclear inclusions (NII) accompanied by a more restricted pattern of neuronal loss. We report here the pathologic findings in a 13-year-old boy who died after a 6-year clinical history of progressive ataxia, extrapyramidal manifestations, and lower motor neuron abnormalities. Histological evaluation of the brain revealed widespread NII in most neurons. Marked loss of cerebellar Purkinje cells and neurons in the dentate nucleus, red nucleus, and spinal cord anterior horns was accompanied by a modest astrocytosis. Because of the abundance of NII and the absence of a relationship between NII and neuronal loss or microglial activation, we conclude that loss of cerebellar, brainstem, and spinal cord neurons reflects selective neuronal vulnerability. NII were immunoreactive for ubiquitin, glucocorticoid receptor, and SUMO-1, a small, ubiquitin-like protein purportedly involved in protein transport and gene transcription. NII were non-reactive for polyglutamine (1C2), TATA binding protein, promyelocytic leukemia protein, heat shock protein 90, tau, alpha-synuclein, neurofilament, and beta amyloid. The moderate ubiquitin and strong SUMO-1 staining of NII in juvenile cases is the reverse of the pattern noted in adult diseases, suggesting the two age groups are pathogenically distinct. We suggest that juvenile NIID is a spinocerebellar brainstem ataxic disease possibly related to an abnormality in SUMOylation.
{"title":"Neuronal Intranuclear Inclusion Disease Without Polyglutamine Inclusions in a Child","authors":"K. McFadden, R. Hamilton, S. Insalaco, L. Lavine, M. Al-Mateen, Guoji Wang, C. Wiley","doi":"10.1097/01.jnen.0000166798.69322.4e","DOIUrl":"https://doi.org/10.1097/01.jnen.0000166798.69322.4e","url":null,"abstract":"Neuronal intranuclear inclusion disease (NIID) is a rare and heterogeneous group of slowly progressive neurodegenerative disorders characterized by the widespread presence of eosinophilic neuronal intranuclear inclusions (NII) accompanied by a more restricted pattern of neuronal loss. We report here the pathologic findings in a 13-year-old boy who died after a 6-year clinical history of progressive ataxia, extrapyramidal manifestations, and lower motor neuron abnormalities. Histological evaluation of the brain revealed widespread NII in most neurons. Marked loss of cerebellar Purkinje cells and neurons in the dentate nucleus, red nucleus, and spinal cord anterior horns was accompanied by a modest astrocytosis. Because of the abundance of NII and the absence of a relationship between NII and neuronal loss or microglial activation, we conclude that loss of cerebellar, brainstem, and spinal cord neurons reflects selective neuronal vulnerability. NII were immunoreactive for ubiquitin, glucocorticoid receptor, and SUMO-1, a small, ubiquitin-like protein purportedly involved in protein transport and gene transcription. NII were non-reactive for polyglutamine (1C2), TATA binding protein, promyelocytic leukemia protein, heat shock protein 90, tau, alpha-synuclein, neurofilament, and beta amyloid. The moderate ubiquitin and strong SUMO-1 staining of NII in juvenile cases is the reverse of the pattern noted in adult diseases, suggesting the two age groups are pathogenically distinct. We suggest that juvenile NIID is a spinocerebellar brainstem ataxic disease possibly related to an abnormality in SUMOylation.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"64 5 1","pages":"545-552"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77825095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-06-01DOI: 10.1097/01.jnen.0000166128.51154.09
Lisa Nowoslawski, B. Klocke, K. Roth
Ethanol is a potent neurotoxin particularly for the developing nervous system. Intrauterine exposure to ethanol during the last trimester of human gestation can produce a broad spectrum of neuropathologic consequences. This period of human brain development is roughly equivalent to the first week of rodent postnatal life and acute exposure of neonatal mice to ethanol produces massive neuronal apoptosis throughout the brain. We have previously demonstrated that ethanol-induced neuron apoptosis is critically dependent on expression of Bax, a proapoptotic member of the Bcl-2 family. To further define the molecular pathway regulating ethanol-induced neuron apoptosis, we analyzed the effects of acute ethanol exposure on cerebellar internal granule cell neurons both in vivo and in vitro. Ethanol produced extensive Bax-dependent caspase-3 activation and neuron apoptosis in the cerebellar internal granule cell layer, which was maximal at approximately 6 hours postadministration. This effect was recapitulated in vitro and required new gene transcription, protein translation, Bax expression, and caspase activation. Ethanol-induced neuron death was independent of p53 expression and was unaffected by deficiency in the proapoptotic Bcl-2 family members Bid or Bad. These studies indicate that ethanol activates an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects of human fetal alcohol exposure.
{"title":"Molecular Regulation of Acute Ethanol-Induced Neuron Apoptosis","authors":"Lisa Nowoslawski, B. Klocke, K. Roth","doi":"10.1097/01.jnen.0000166128.51154.09","DOIUrl":"https://doi.org/10.1097/01.jnen.0000166128.51154.09","url":null,"abstract":"Ethanol is a potent neurotoxin particularly for the developing nervous system. Intrauterine exposure to ethanol during the last trimester of human gestation can produce a broad spectrum of neuropathologic consequences. This period of human brain development is roughly equivalent to the first week of rodent postnatal life and acute exposure of neonatal mice to ethanol produces massive neuronal apoptosis throughout the brain. We have previously demonstrated that ethanol-induced neuron apoptosis is critically dependent on expression of Bax, a proapoptotic member of the Bcl-2 family. To further define the molecular pathway regulating ethanol-induced neuron apoptosis, we analyzed the effects of acute ethanol exposure on cerebellar internal granule cell neurons both in vivo and in vitro. Ethanol produced extensive Bax-dependent caspase-3 activation and neuron apoptosis in the cerebellar internal granule cell layer, which was maximal at approximately 6 hours postadministration. This effect was recapitulated in vitro and required new gene transcription, protein translation, Bax expression, and caspase activation. Ethanol-induced neuron death was independent of p53 expression and was unaffected by deficiency in the proapoptotic Bcl-2 family members Bid or Bad. These studies indicate that ethanol activates an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects of human fetal alcohol exposure.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"22 1","pages":"490-497"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75917691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-06-01DOI: 10.1097/01.jnen.0000166130.35907.14
K. Sugie, S. Noguchi, Y. Kozuka, E. Arikawa-Hirasawa, Mikihito Tanaka, Chuanzhu Yan, P. Saftig, K. von Figura, M. Hirano, S. Ueno, I. Nonaka, I. Nishino
Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, and the mechanism of AVSF formation is not known. To address these issues, we have performed detailed histologic studies of myopathies with AVSF and other AVMs. In Danon disease and related AVMs, at the light microscopic level, autophagic vacuoles appeared to be accumulations of lysosomes, which, by electron microscopy consisted of clusters of autophagic vacuoles, indicative of autolysosomes. Some autolysosomes were surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity, and basal lamina. In Danon disease, the number of fibers with AVSF increased linearly with age while the number with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. Most of the AVSF form enclosed spaces, indicating that the vacuolar membranes may be formed in situ rather than through sarcolemmal indentation. This unique intracytoplasmic membrane structure was not found in other AVMs. In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs.
{"title":"Autophagic Vacuoles with Sarcolemmal Features Delineate Danon Disease and Related Myopathies","authors":"K. Sugie, S. Noguchi, Y. Kozuka, E. Arikawa-Hirasawa, Mikihito Tanaka, Chuanzhu Yan, P. Saftig, K. von Figura, M. Hirano, S. Ueno, I. Nonaka, I. Nishino","doi":"10.1097/01.jnen.0000166130.35907.14","DOIUrl":"https://doi.org/10.1097/01.jnen.0000166130.35907.14","url":null,"abstract":"Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, and the mechanism of AVSF formation is not known. To address these issues, we have performed detailed histologic studies of myopathies with AVSF and other AVMs. In Danon disease and related AVMs, at the light microscopic level, autophagic vacuoles appeared to be accumulations of lysosomes, which, by electron microscopy consisted of clusters of autophagic vacuoles, indicative of autolysosomes. Some autolysosomes were surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity, and basal lamina. In Danon disease, the number of fibers with AVSF increased linearly with age while the number with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. Most of the AVSF form enclosed spaces, indicating that the vacuolar membranes may be formed in situ rather than through sarcolemmal indentation. This unique intracytoplasmic membrane structure was not found in other AVMs. In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"64 1","pages":"513-522"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83116859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-06-01DOI: 10.1097/01.jnen.0000166127.43530.05
G. Kanmogne, Charles Primeaux, P. Grammas
Breakdown of the blood-brain barrier (BBB) is commonly seen in patients with HIV-associated dementia (HAD) despite the lack of productive infection of the brain endothelium. It is likely that secreted viral products play a major role in BBB damage and the development of HAD. The objective of this study is to determine the effects of gp120 proteins on brain endothelial cell permeability and junctional protein expression. Our results showed that treatment of cultured human brain endothelial cells with gp120 for 24 hours results in increased permeability of the endothelial monolayer. Also, gp120 proteins caused disruption and downregulation of the tight junction proteins ZO-1, ZO-2, and occludin in these cells. Other junctional proteins such as claudin-1 and claudin-5 were unaffected by gp120 treatment. These data demonstrate that HIV gp120 proteins alter both the functional and molecular properties of the BBB, which could increase trafficking of HIV, infected cells, and toxic humoral factors into the central nervous system and contribute to the pathogenesis of HAD.
{"title":"HIV-1 gp120 Proteins Alter Tight Junction Protein Expression and Brain Endothelial Cell Permeability: Implications for the Pathogenesis of HIV-Associated Dementia","authors":"G. Kanmogne, Charles Primeaux, P. Grammas","doi":"10.1097/01.jnen.0000166127.43530.05","DOIUrl":"https://doi.org/10.1097/01.jnen.0000166127.43530.05","url":null,"abstract":"Breakdown of the blood-brain barrier (BBB) is commonly seen in patients with HIV-associated dementia (HAD) despite the lack of productive infection of the brain endothelium. It is likely that secreted viral products play a major role in BBB damage and the development of HAD. The objective of this study is to determine the effects of gp120 proteins on brain endothelial cell permeability and junctional protein expression. Our results showed that treatment of cultured human brain endothelial cells with gp120 for 24 hours results in increased permeability of the endothelial monolayer. Also, gp120 proteins caused disruption and downregulation of the tight junction proteins ZO-1, ZO-2, and occludin in these cells. Other junctional proteins such as claudin-1 and claudin-5 were unaffected by gp120 treatment. These data demonstrate that HIV gp120 proteins alter both the functional and molecular properties of the BBB, which could increase trafficking of HIV, infected cells, and toxic humoral factors into the central nervous system and contribute to the pathogenesis of HAD.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"16 1","pages":"498-505"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77197307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-05-01DOI: 10.1097/01.JNEN.0000162614.70295.BA
A. Judkins, P. Burger, R. Hamilton, B. Kleinschmidt-DeMasters, A. Perry, S. Pomeroy, M. Rosenblum, A. Yachnis, Holly Zhou, L. Rorke, J. Biegel
Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) and choroid plexus carcinoma (CPC) are rare, highly malignant tumors that predominantly arise in infants and young children. Overlapping clinical, histologic, ultrastructural, or immunophenotypic features may obscure the diagnosis in some cases. AT/RT is characterized by deletions and/or mutations of the INI1 tumor-suppressor gene on chromosome band 22q11.2. We have recently developed an INI1 immunohistochemical staining assay. Negative staining of tumor cells resulting from inactivation of the INI1 gene is a consistent feature of AT/RT. Mutations of INI1 in some CPCs have been reported. The purpose of the present study was to determine if immunohistochemical staining with an INI1 antibody would provide a sensitive means of distinguishing between CPC and AT/RT. We examined 28 tumors with a submitted diagnosis of CPC. Twenty-one CPCs showed retained expression of INI1 and seven tumors showed loss of INI1 expression. Cytogenetic, FISH, and/or INI1 mutation results were also available for 13 tumors. In three of the seven cases, monosomy 22 was the only cytogenetic abnormality, suggestive of AT/RT. However, monosomy 22 was also identified in 3 tumors with complex karyotypes that retained INI1 expression. The 7 tumors that were immunonegative for INI1 had features that were consistent with AT/RT. Immunostaining for INI1 protein is retained in the majority of CPC and is lost in AT/RT. This expression pattern seems to better define the 2 groups of tumors than does light or electron microscopy, routine immunohistochemistry, or cytogenetic analysis alone.
{"title":"INI1 Protein Expression Distinguishes Atypical Teratoid/Rhabdoid Tumor from Choroid Plexus Carcinoma","authors":"A. Judkins, P. Burger, R. Hamilton, B. Kleinschmidt-DeMasters, A. Perry, S. Pomeroy, M. Rosenblum, A. Yachnis, Holly Zhou, L. Rorke, J. Biegel","doi":"10.1097/01.JNEN.0000162614.70295.BA","DOIUrl":"https://doi.org/10.1097/01.JNEN.0000162614.70295.BA","url":null,"abstract":"Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) and choroid plexus carcinoma (CPC) are rare, highly malignant tumors that predominantly arise in infants and young children. Overlapping clinical, histologic, ultrastructural, or immunophenotypic features may obscure the diagnosis in some cases. AT/RT is characterized by deletions and/or mutations of the INI1 tumor-suppressor gene on chromosome band 22q11.2. We have recently developed an INI1 immunohistochemical staining assay. Negative staining of tumor cells resulting from inactivation of the INI1 gene is a consistent feature of AT/RT. Mutations of INI1 in some CPCs have been reported. The purpose of the present study was to determine if immunohistochemical staining with an INI1 antibody would provide a sensitive means of distinguishing between CPC and AT/RT. We examined 28 tumors with a submitted diagnosis of CPC. Twenty-one CPCs showed retained expression of INI1 and seven tumors showed loss of INI1 expression. Cytogenetic, FISH, and/or INI1 mutation results were also available for 13 tumors. In three of the seven cases, monosomy 22 was the only cytogenetic abnormality, suggestive of AT/RT. However, monosomy 22 was also identified in 3 tumors with complex karyotypes that retained INI1 expression. The 7 tumors that were immunonegative for INI1 had features that were consistent with AT/RT. Immunostaining for INI1 protein is retained in the majority of CPC and is lost in AT/RT. This expression pattern seems to better define the 2 groups of tumors than does light or electron microscopy, routine immunohistochemistry, or cytogenetic analysis alone.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"16 1","pages":"391-397"},"PeriodicalIF":0.0,"publicationDate":"2005-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75534366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-05-01DOI: 10.1097/01.JNEN.0000162669.85797.5A
A. Ogino, A. Yoshino, Y. Katayama, Takao Watanabe, T. Ota, C. Komine, Takakazu Yokoyama, T. Fukushima
Pituitary adenomas are common benign intracranial neoplasms. However, their tumorigenesis is not yet clearly defined. Inactivation of genes involved in the negative cell-cycle regulatory p15INK4b-p16INK4a-cyclin D/CDK4-RB1-mediated pathway (RB1 pathway) is one of the most common and important mechanisms in the growth advantage of tumor cells. Recently, much attention has been focused on the importance of alternative mechanisms of gene inactivation, particularly promoter hypermethylation in the transcriptional silencing of such tumor-suppressor genes. Based on the rare occurrence of inactivation by gene mutations and deletions of the RB1 pathway in pituitary adenomas, we investigated the deregulation of the RB1 pathway in 42 sporadic human pituitary adenomas, especially focusing on the methylation status of this pathway as determined by a methylation-specific polymerase chain reaction assay. Homozygous deletion of the p15INK4b or p16INK4a gene was detected in one adenoma each. Amplification of the CDK4 gene was not apparent in any of the pituitary adenomas presently examined. Promoter hypermethylation of the p15INK4b, p16INK4a, and RB1 genes was detected in 15 (35.7%), 30 (71.4%), and 12 (28.6%) of the adenomas, respectively. Promoter hypermethylation of the p15INK4b gene coincided with p16INK4a alteration and/or RB1 methylation, whereas p16INK4a and RB1 methylations tended to be mutually exclusive (p = 0.019). Thus, the vast majority of the adenomas (38 of 42, 90.5%) displayed alterations of the RB1 pathway. None of the clinicopathologic features, including the proliferation cell index, was significantly correlated with any particular methylation status. Our results suggest that inactivation of the RB1 pathway may play a causal role in pituitary tumorigenesis, with hypermethylation of the p16INK4a gene being the most common deregulation, and further provide evidence that RB1 and p16INK4a methylations tend to be mutually exclusive but occasionally coincide with p15INK4b methylation.
{"title":"The p15INK4b/p16INK4a/RB1 Pathway Is Frequently Deregulated in Human Pituitary Adenomas","authors":"A. Ogino, A. Yoshino, Y. Katayama, Takao Watanabe, T. Ota, C. Komine, Takakazu Yokoyama, T. Fukushima","doi":"10.1097/01.JNEN.0000162669.85797.5A","DOIUrl":"https://doi.org/10.1097/01.JNEN.0000162669.85797.5A","url":null,"abstract":"Pituitary adenomas are common benign intracranial neoplasms. However, their tumorigenesis is not yet clearly defined. Inactivation of genes involved in the negative cell-cycle regulatory p15INK4b-p16INK4a-cyclin D/CDK4-RB1-mediated pathway (RB1 pathway) is one of the most common and important mechanisms in the growth advantage of tumor cells. Recently, much attention has been focused on the importance of alternative mechanisms of gene inactivation, particularly promoter hypermethylation in the transcriptional silencing of such tumor-suppressor genes. Based on the rare occurrence of inactivation by gene mutations and deletions of the RB1 pathway in pituitary adenomas, we investigated the deregulation of the RB1 pathway in 42 sporadic human pituitary adenomas, especially focusing on the methylation status of this pathway as determined by a methylation-specific polymerase chain reaction assay. Homozygous deletion of the p15INK4b or p16INK4a gene was detected in one adenoma each. Amplification of the CDK4 gene was not apparent in any of the pituitary adenomas presently examined. Promoter hypermethylation of the p15INK4b, p16INK4a, and RB1 genes was detected in 15 (35.7%), 30 (71.4%), and 12 (28.6%) of the adenomas, respectively. Promoter hypermethylation of the p15INK4b gene coincided with p16INK4a alteration and/or RB1 methylation, whereas p16INK4a and RB1 methylations tended to be mutually exclusive (p = 0.019). Thus, the vast majority of the adenomas (38 of 42, 90.5%) displayed alterations of the RB1 pathway. None of the clinicopathologic features, including the proliferation cell index, was significantly correlated with any particular methylation status. Our results suggest that inactivation of the RB1 pathway may play a causal role in pituitary tumorigenesis, with hypermethylation of the p16INK4a gene being the most common deregulation, and further provide evidence that RB1 and p16INK4a methylations tend to be mutually exclusive but occasionally coincide with p15INK4b methylation.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"36 1","pages":"398-403"},"PeriodicalIF":0.0,"publicationDate":"2005-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82533508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-04-01DOI: 10.1097/01.JNEN.0000159969.13223.31
C. Matsuda, K. Kameyama, K. Tagawa, M. Ogawa, A. Suzuki, S. Yamaji, H. Okamoto, I. Nishino, Y. Hayashi
The dysferlin gene is defective in Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin is a sarcolemmal protein that is implicated in calcium-dependent membrane repair. Affixin (β-parvin) is a novel, integrin-linked kinase-binding protein that is involved in the linkage between integrin and the cytoskeleton. Here we show that affixin is a dysferlin binding protein that colocalizes with dysferlin at the sarcolemma of normal human skeletal muscle. The immunoreactivity of affixin was reduced in sarcolemma of MM and LGMD2B muscles, although the total amount of the affixin protein was normal. Altered immunoreactivity of affixin was also observed in other muscle diseases including LGMD1C, where both affixin and dysferlin showed quite similar changes with a reduction of sarcolemmal staining with or without cytoplasmic accumulations. Colocalization of dysferlin and affixin was confirmed by immunofluorescence analysis using dysferlin-expressing C2 myoblasts. Wild-type and mutant dysferlin colocalized with endogenous affixin. The interaction of dysferlin and affixin was confirmed by immunoprecipitation study using normal human and mouse skeletal muscles. Using immunoprecipitation with deletion mutants of dysferlin, we have identified that C-terminal region of dysferlin is an apparent binding site for affixin. We also found N-terminal calponin homology domain of affixin as a binding site for dysferlin. Our results suggest that affixin may participate in membrane repair with dysferlin.
{"title":"Dysferlin Interacts with Affixin (β-Parvin) at the Sarcolemma","authors":"C. Matsuda, K. Kameyama, K. Tagawa, M. Ogawa, A. Suzuki, S. Yamaji, H. Okamoto, I. Nishino, Y. Hayashi","doi":"10.1097/01.JNEN.0000159969.13223.31","DOIUrl":"https://doi.org/10.1097/01.JNEN.0000159969.13223.31","url":null,"abstract":"The dysferlin gene is defective in Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin is a sarcolemmal protein that is implicated in calcium-dependent membrane repair. Affixin (β-parvin) is a novel, integrin-linked kinase-binding protein that is involved in the linkage between integrin and the cytoskeleton. Here we show that affixin is a dysferlin binding protein that colocalizes with dysferlin at the sarcolemma of normal human skeletal muscle. The immunoreactivity of affixin was reduced in sarcolemma of MM and LGMD2B muscles, although the total amount of the affixin protein was normal. Altered immunoreactivity of affixin was also observed in other muscle diseases including LGMD1C, where both affixin and dysferlin showed quite similar changes with a reduction of sarcolemmal staining with or without cytoplasmic accumulations. Colocalization of dysferlin and affixin was confirmed by immunofluorescence analysis using dysferlin-expressing C2 myoblasts. Wild-type and mutant dysferlin colocalized with endogenous affixin. The interaction of dysferlin and affixin was confirmed by immunoprecipitation study using normal human and mouse skeletal muscles. Using immunoprecipitation with deletion mutants of dysferlin, we have identified that C-terminal region of dysferlin is an apparent binding site for affixin. We also found N-terminal calponin homology domain of affixin as a binding site for dysferlin. Our results suggest that affixin may participate in membrane repair with dysferlin.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"33 1","pages":"334-340"},"PeriodicalIF":0.0,"publicationDate":"2005-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77599645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-04-01DOI: 10.1097/01.JNEN.0000159845.12014.AF
T. Abel, S. Baker, M. M. Fraser, T. Tihan, J. Nelson, A. Yachnis, J. Bouffard, H. Mena, P. Burger, C. Eberhart
Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.
{"title":"Lhermitte-Duclos Disease: A Report of 31 Cases with Immunohistochemical Analysis of the PTEN/AKT/mTOR Pathway","authors":"T. Abel, S. Baker, M. M. Fraser, T. Tihan, J. Nelson, A. Yachnis, J. Bouffard, H. Mena, P. Burger, C. Eberhart","doi":"10.1097/01.JNEN.0000159845.12014.AF","DOIUrl":"https://doi.org/10.1097/01.JNEN.0000159845.12014.AF","url":null,"abstract":"Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"4 1","pages":"341-349"},"PeriodicalIF":0.0,"publicationDate":"2005-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74694527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-04-01DOI: 10.1097/01.JNEN.0000159844.17852.45
A. Compton, S. Cooper, P. Hill, N. Yang, S. Froehner, K. North
The syntrophins and α-dystrobrevin form a subcomplex with dystrophin at the skeletal muscle membrane, and are also highly concentrated at the neuromuscular synapse. Here we demonstrate that the different syntrophins and α-dystrobrevin isoforms have distinct expression patterns during human skeletal muscle development, and are differentially affected by loss of dystrophin anchorage and denervation in human neuromuscular disease. During normal fetal development, and in Duchenne muscular dystrophy and denervation disorders, α1-syntrophin and α-dystrobrevin are absent or markedly reduced at the sarcolemmal membrane. β1-Syntrophin is the predominant syntrophin isoform expressed at the muscle membrane during development, and it undergoes upregulation in response to loss of α1-syntrophin in Duchenne muscular dystrophy and in denervation. Upregulation of β1-syntrophin in neuromuscular disorders is associated with re-expression of the fetal nicotinic acetylcholine receptor γ-subunit, cardiac actin, and neonatal myosin, suggesting reversion of muscle fibers to an immature phenotype. We show that denervation specifically affects expression of the syntrophin-dystrobrevin subcomplex and does not affect levels or localization of other members of the dystrophin-associated protein complex. Our results confirm that dystrophin is required for anchorage of the syntrophin-dystrobrevin subcomplex and suggest that expression of the syntrophin-dystrobrevin complex may be independently regulated through neuromuscular transmission.
{"title":"The Syntrophin-Dystrobrevin Subcomplex in Human Neuromuscular Disorders","authors":"A. Compton, S. Cooper, P. Hill, N. Yang, S. Froehner, K. North","doi":"10.1097/01.JNEN.0000159844.17852.45","DOIUrl":"https://doi.org/10.1097/01.JNEN.0000159844.17852.45","url":null,"abstract":"The syntrophins and α-dystrobrevin form a subcomplex with dystrophin at the skeletal muscle membrane, and are also highly concentrated at the neuromuscular synapse. Here we demonstrate that the different syntrophins and α-dystrobrevin isoforms have distinct expression patterns during human skeletal muscle development, and are differentially affected by loss of dystrophin anchorage and denervation in human neuromuscular disease. During normal fetal development, and in Duchenne muscular dystrophy and denervation disorders, α1-syntrophin and α-dystrobrevin are absent or markedly reduced at the sarcolemmal membrane. β1-Syntrophin is the predominant syntrophin isoform expressed at the muscle membrane during development, and it undergoes upregulation in response to loss of α1-syntrophin in Duchenne muscular dystrophy and in denervation. Upregulation of β1-syntrophin in neuromuscular disorders is associated with re-expression of the fetal nicotinic acetylcholine receptor γ-subunit, cardiac actin, and neonatal myosin, suggesting reversion of muscle fibers to an immature phenotype. We show that denervation specifically affects expression of the syntrophin-dystrobrevin subcomplex and does not affect levels or localization of other members of the dystrophin-associated protein complex. Our results confirm that dystrophin is required for anchorage of the syntrophin-dystrobrevin subcomplex and suggest that expression of the syntrophin-dystrobrevin complex may be independently regulated through neuromuscular transmission.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"68 1","pages":"350-361"},"PeriodicalIF":0.0,"publicationDate":"2005-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75246024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Targeted gene disruptions have revealed significant roles for caspase family members in the regulation of neuronal programmed cell death. Both caspase-3- and caspase-9-deficient mice exhibit a variably severe neurodevelopmental phenotype that may include marked ventricular zone expansion, exencephaly, and ectopic neuronal structures. Our previous studies of caspase-3- and caspase-9-deficient mice were performed using mice on mixed genetic backgrounds, raising the possibility that strain-specific genetic factors influence the effects of caspase deficiency on nervous system development. To directly test this hypothesis, we backcrossed the caspase-3 mutation for 7–10 generations onto pure C57BL/6J and 129X1/SvJ genetic backgrounds. Caspase-3-deficient 129X1/SvJ mice were uniformly and severely affected. These mice died during the perinatal period and exhibited marked neural precursor cell expansion and exencephaly. In contrast, caspase-3-deficient C57BL/6J mice reached adulthood, were fertile and showed minimal brain pathology. Intercrosses of C57BL/6J and 129X1/SvJ mutants revealed that the vast majority of caspase-3−/− F1 mice displayed the severe 129X1/SvJ-“like” phenotype. These findings are consistent with an incompletely penetrant strain-dependent genetic modifier (or modifiers) that alters the neurodevelopmental consequences of caspase-3 deficiency. Since caspase-9- and Apaf-1-deficient mice also display variably severe developmental neuropathology, this strain-dependent modifier(s) may be involved in the activation of a caspase-independent death pathway; alternatively, strain-dependent compensatory caspase activation and/or its inhibition may influence the severity of the caspase-3-deficient neuronal phenotype.
{"title":"Strain‐Dependent Neurodevelopmental Abnormalities in Caspase‐3‐Deficient Mice","authors":"B. Klocke, C. D'Sa, R. Flavell, K. Roth","doi":"10.1093/JNEN/61.8.673","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.673","url":null,"abstract":"Targeted gene disruptions have revealed significant roles for caspase family members in the regulation of neuronal programmed cell death. Both caspase-3- and caspase-9-deficient mice exhibit a variably severe neurodevelopmental phenotype that may include marked ventricular zone expansion, exencephaly, and ectopic neuronal structures. Our previous studies of caspase-3- and caspase-9-deficient mice were performed using mice on mixed genetic backgrounds, raising the possibility that strain-specific genetic factors influence the effects of caspase deficiency on nervous system development. To directly test this hypothesis, we backcrossed the caspase-3 mutation for 7–10 generations onto pure C57BL/6J and 129X1/SvJ genetic backgrounds. Caspase-3-deficient 129X1/SvJ mice were uniformly and severely affected. These mice died during the perinatal period and exhibited marked neural precursor cell expansion and exencephaly. In contrast, caspase-3-deficient C57BL/6J mice reached adulthood, were fertile and showed minimal brain pathology. Intercrosses of C57BL/6J and 129X1/SvJ mutants revealed that the vast majority of caspase-3−/− F1 mice displayed the severe 129X1/SvJ-“like” phenotype. These findings are consistent with an incompletely penetrant strain-dependent genetic modifier (or modifiers) that alters the neurodevelopmental consequences of caspase-3 deficiency. Since caspase-9- and Apaf-1-deficient mice also display variably severe developmental neuropathology, this strain-dependent modifier(s) may be involved in the activation of a caspase-independent death pathway; alternatively, strain-dependent compensatory caspase activation and/or its inhibition may influence the severity of the caspase-3-deficient neuronal phenotype.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"79 1","pages":"673–677"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82289528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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