Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3.
OBJECTIVE
We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3.


METHODS
Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease.


RESULTS
NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes.


CONCLUSIONS
Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.
Evert
B O
BO
Department of Neurology, University of Bonn, Germany.
Schelhaas
J
J
Fleischer
H
H
de Vos
R A I
RA
Brunt
E R
ER
Stenzel
W
W
Klockgether
T
T
Wüllner
U
U
D000368:Aged; D000067699:Ataxin-3; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017827:Machado-Joseph Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
D015415:Biomarkers; C497252:CEBPD protein, human; D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; C092341:ATXN3 protein, human; D000067699:Ataxin-3