Two populations of neuronal intranuclear inclusions in SCA7 differ in size and promyelocytic leukaemia protein content.
Spinocerebellar ataxia type 7 (SCA7) is a hereditary progressive cerebellar ataxia with retinal degeneration associated with an abnormally expanded polyglutamine stretch. Neuronal intranuclear inclusions (NIIs), as in other polyglutamine diseases, are pathological hallmarks of these disorders. NIIs in polyglutamine diseases contain not only the protein with the expanded polyglutamine stretch but also other types of proteins. Several chaperone proteins related to the ubiquitin proteasome pathway, transcription factors and nuclear matrix proteins have been detected in NIIs. The composition of NIIs might reflect the process of NII formation and part of the pathogenesis of these diseases. To investigate how these proteins relate to the pathogenesis of SCA7, we performed immunohistochemical analyses of the composition of NIIs in two cases of SCA7. We demonstrated that there are two types of NIIs in SCA7 that differ in size and immunoreactivity to promyelocytic leukaemia protein (PML), one of the essential components of nuclear bodies (NBs; also called PML oncogenic domains). Small and large NIIs contained ataxin-7, human DnaJ homologue 2 (HDJ-2) and proteasome subunit 19S. In contrast, PML was found only in small NIIs. CREB-binding protein (CBP), another component of NBs, was distributed like PML in NIIs. Our results suggest that NIIs are formed by the accumulation of ataxin-7 in NBs, which become enlarged as they recruit related proteins.
Takahashi
Junko
J
Laboratoire de Neuropathologie Raymond Escourolle, Paris, France.
Fujigasaki
Hiroto
H
Zander
Cecilia
C
El Hachimi
Khalid H
KH
Stevanin
Giovanni
G
Dürr
Alexandra
A
Lebre
Anne-Sophie
AS
Yvert
Gaël
G
Trottier
Yvon
Y
de Thé
Hugues
H
Hauw
Jean-Jacques
JJ
Duyckaerts
Charles
C
Brice
Alexis
A
D000328:Adult; D000067719:Ataxin-7; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D013132:Spinocerebellar Degenerations / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human