Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3.
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.
Zander
C
C
INSERM U289, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris, Cedex 13, France.
Takahashi
J
J
El Hachimi
K H
KH
Fujigasaki
H
H
Albanese
V
V
Lebre
A S
AS
Stevanin
G
G
Duyckaerts
C
C
Brice
A
A
D000328:Adult; D000067699:Ataxin-3; D000067719:Ataxin-7; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D006360:Heat-Shock Proteins; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex