Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain.
Machado-Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin-3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin-3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell-specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.
Paulson
H L
HL
Department of Pharmacology, University of Pennsylvania, Philadelphia 19104, USA.
Das
S S
SS
Crino
P B
PB
Perez
M K
MK
Patel
S C
SC
Gotsdiner
D
D
Fischbeck
K H
KH
Pittman
R N
RN
D000328:Adult; D000067699:Ataxin-3; D001284:Atrophy; D001483:Base Sequence; D001923:Brain Chemistry; D002460:Cell Line; D002467:Cell Nucleus / Q000473:pathology; D003593:Cytoplasm / Q000737:chemistry*; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000235:genetics; D009687:Nuclear Proteins; D011149:Pons / Q000473:pathology; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins; D013116:Spinal Cord / Q000473:pathology; D014162:Transfection
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3