title: Promyelocytic leukemia protein is redistributed during the formation of intranuclear inclusions independent of polyglutamine expansion: an immunohistochemical study on Marinesco bodies.
abstract: Marinesco bodies (MBs) are ubiquitinated intranuclear inclusions observed in nigral pigmented neurons. They increase in number during aging, and their formation is considered to represent a cellular reaction to stress, but is not always associated with neuronal degeneration. We conducted immunohistochemical studies on MBs abundant in myotonic dystrophy brains and compared their nature with that of neuronal intranuclear inclusions (NIIs) in polyglutamine diseases. First, we examined the relationship between MBs and polyglutamine proteins and demonstrated that one of the polyglutamine proteins, ataxin-3, as well as a 19S proteasomal protein, was preferentially recruited into MBs even in the absence of expanded polyglutamine. This indicates that an alternative mechanism during the formation of MBs that is not related to polyglutamine expansion or neuronal degeneration may recruit ataxin-3 into nuclear inclusions in a protein-specific manner. Secondly, we investigated the relationship between MBs and promyelocytic leukemia protein (PML), a nuclear matrix-associated protein that is normally localized to intranuclear punctate structures (PML nuclear bodies) and is known to reorganize itself in association with polyglutamine aggregation. In nigral pigmented neurons in myotonic dystrophy, spherical, hemispherical or rod-like PML-immunoreactive structures, in addition to punctate structures, were observed in their nuclei. Similar PML redistribution was also observed in nigral pigmented neurons in aged controls and cases of hepatic encephalopathy, 2 other conditions in which abundant MBs are formed. Double immunofluorescence study revealed that these PML-positive structures undergo morphological changes in association with ubiquitin accumulation during MB formation. It is therefore indicated that PML reorganization does not represent a specific nuclear event involved in the pathogenesis of polyglutamine diseases, but may commonly occur during the formation of intranuclear inclusions as a reaction against various stresses that involve the ubiquitin-proteasome pathway.
authors.affiliation: Department of Pediatrics, Metropolitan Fuchu Medical Center for Severe Motor and Intellectual Disabilities, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kumada
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchihara
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Toshio
authors.initials: T
authors.lastname: Mizutani
authors.forename: Masaya
authors.initials: M
authors.lastname: Oda
mesh_terms: D000328:Adult; D000368:Aged; D000067699:Ataxin-3; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006501:Hepatic Encephalopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D000071156:Promyelocytic Leukemia Protein; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C070576:PML protein, human; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex