Alpha-synuclein immunoreactivity of huntingtin polyglutamine aggregates in striatum and cortex of Huntington's disease patients and transgenic mouse models.
Polyglutamine expansions in proteins are implicated in at least eight inherited neurodegenerative disorders, including Huntington's disease. These mutant proteins can form aggregates within the nucleus and processes of neurons possibly due to misfolding of the proteins. Polyglutamine aggregates are ubiquitinated and sequester molecular chaperone proteins and proteasome components. To investigate other protein components of polyglutamine aggregates, cerebral cortex and striata from patients with Huntington's disease and full-length cDNA transgenic mouse models for this disease were examined immunohistochemically for alpha-synuclein reactivity. Our findings demonstrate that alpha-synuclein can be used as a marker for huntingtin polyglutamine aggregates in both human and mice. Moreover in the HD transgenic mice, the intensity of immunoreactivity increases with age. The significance of recruitment of alpha-synuclein into huntingtin aggregates and its translocation away from the synapses remains to be determined. We propose that aberrant interaction of mutant huntingtin with other proteins, including alpha-synuclein, may influence disease progression.
Charles
V
V
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mezey
E
E
Reddy
P H
PH
Dehejia
A
A
Young
T A
TA
Polymeropoulos
M H
MH
Brownstein
M J
MJ
Tagle
D A
DA
D020816:Amino Acid Motifs; D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry* / Q000473:pathology; D003342:Corpus Striatum / Q000737:chemistry* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis* / Q000378:metabolism; D010455:Peptides / Q000032:analysis* / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis* / Q000378:metabolism; D017510:Protein Folding; D011817:Rabbits; D051843:Synucleins; D051844:alpha-Synuclein
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D010750:Phosphoproteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; C097188:polyglutamine