Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 66, Issue 4, Pages 313-320Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/nen.0b013e318040b2c8
Keywords
huntingtin; Huntington disease; inclusion bodies; neurodegenerative disease; proteolytic processing
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Funding
- NINDS NIH HHS [NS38144, 1 P01 NS16375, NS 34177] Funding Source: Medline
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Huntington disease (HD) is caused by the expansion of a glutamine (Q) repeat near the N terminus of huntingtin (btt), resulting in altered conformation of the mutant protein to produce, most prominently in brain neurons, nuclear and cytoplasmic inclusion pathology. The inclusions and associated diffuse accumulation of mutant htt in nuclei are composed of N-terminal fragments of mutant protein. Here, we used a panel of peptide antibodies to characterize the htt protein pathologies in brain tissues from human HD, and a transgenic mouse model created by expressing the first 171 amino acids of human btt with 82Q (htt-N171-82Q). In tissues from both sources, htt pathologic features in nuclei were detected by antibodies to htt peptides 1-17 and 81-90 but not 115-129 (wildtype huntingtin numbering with 23 repeats). Human HEK 293 cells transfected with expression vectors that encode either the N-terminal 233 amino acids of human htt (htt-N233-82Q) or htt-N171-18Q accumulated smaller N-terminal fragments with antibody-birt ding characteristics identical to those of pathologic peptides. We conclude that the mutant htt peptides that accumulate in pathologic structures of human HD and httN 171-82Q in mice are produced by similar, yet to be defined, proteolytic events in a region of the protein near or within amino acids 90-115.
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