Polyglutamine and polyalanine expansions in ataxin7 result in different types of aggregation and levels of toxicity.
Spinocerebellar ataxia type 7 (SCA7) is caused by expansion of a (CAG)n repeat in the ataxin7 gene, resulting in an abnormally long polyglutamine polyQ tract in the translated protein that aggregates in the form of neuronal intranuclear inclusions. Polyalanine (polyA) stretches, implicated in several genetic disorders, also appear to aggregate. To investigate the role of the aggregates in the pathologies, we compared the effects of ataxin7 containing a polyA (ataxin7 - 90A) or polyQ (ataxin7 - 100Q) expansion in HEK 293 cells and in primary cultures of rat mesencephalon. Both proteins formed nuclear and perinuclear aggregates that contained molecular chaperones and components of the ubiquitin-proteasome system, suggesting that they were abnormally folded. Ataxin-90A aggregates differed morphologically from ataxin7 - 100Q aggregates, consisted of small and amorphous rather than fibrillar inclusions and were more toxic to mesencephalic neurons, suggesting that toxicity was determined by the type of aggregate rather than the cellular misfolding response.
Latouche
Morwena
M
INSERM U679 (former U289), Neurologie et Thérapeutique Expérimentale, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Fragner
Pascal
P
Martin
Elodie
E
El Hachimi
Khalid H
KH
Zander
Cecilia
C
Sittler
Annie
A
Ruberg
Merle
M
Brice
Alexis
A
Stevanin
Giovanni
G
D000818:Animals; D000067719:Ataxin-7; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D009454:Neurofibrils / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010455:Peptides; C019529:polyalanine; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex