Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human.
Instability of CAG DNA trinucleotide repeats is the mutational mechanism for several neurodegenerative diseases resulting in the expansion of a polyglutamine (polyQ) tract. Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. We examined whether similar features define spinocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human brains and transgenic mouse lines. In SCA2 brains, we found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomical changes observed in ataxin-1[Q80] transgenic lines, ataxin-2[Q58] remained cytoplasmic without detectable ubiquitination.
Huynh
D P
DP
Rose Moss Laboratory for Parkinson's and Neurodegenerative Diseases, CSMC Burns and Allen Research Institute, and Division of Neurology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.
Figueroa
K
K
Hoang
N
N
Pulst
S M
SM
D000818:Animals; D000067528:Ataxins; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D064026:Calbindins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005080:Exercise Test; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000209:etiology* / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D014452:Ubiquitins / Q000096:biosynthesis
D000067528:Ataxins; D064026:Calbindins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins; D064030:S100 Calcium Binding Protein G; D014452:Ubiquitins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D012313:RNA