Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the androgen receptor (AR). We have studied the mutant AR in an in vitro system, and find both aggregation and proteolytic processing of the AR protein to occur in a polyglutamine repeat length-dependent manner. In addition, we find the aberrant metabolism of expanded repeat AR to be coupled to cellular toxicity, indicating a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA.
Merry
D E
DE
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. merryd@mail.med.upenn.edu
Kobayashi
Y
Y
Bailey
C K
CK
Taye
A A
AA
Fischbeck
K H
KH
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D008040:Genetic Linkage; D005973:Glutamine / Q000235:genetics; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D011940:Receptor Aggregation / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection; D014960:X Chromosome
D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D005973:Glutamine