Early changes in Huntington's disease patient brains involve alterations in cytoskeletal and synaptic elements.
Huntington's disease (HD) is caused by a polyglutamine repeat expansion in the N-terminus of the huntingtin protein. Huntingtin is normally present in the cytoplasm where it may interact with structural and synaptic elements. The mechanism of HD pathogenesis remains unknown but studies indicate a toxic gain-of-function possibly through aberrant protein interactions. To investigate whether early degenerative changes in HD involve alterations of cytoskeletal and vesicular components, we examined early cellular changes in the frontal cortex of HD presymptomatic (PS), early pathological grade (grade 1) and late-stage (grade 3 and 4) patients as compared to age-matched controls. Morphologic analysis using silver impregnation revealed a progressive decrease in neuronal fiber density and organization in pyramidal cell layers beginning in presymptomatic HD cases. Immunocytochemical analyses for the cytoskeletal markers alpha -tubulin, microtubule-associated protein 2, and phosphorylated neurofilament demonstrated a concomitant loss of staining in early grade cases. Immunoblotting for synaptic proteins revealed a reduction in complexin 2, which was marked in some grade 1 HD cases and significantly reduced in all late stage cases. Interestingly, we demonstrate that two synaptic proteins, dynamin and PACSIN 1, which were unchanged by immunoblotting, showed a striking loss by immunocytochemistry beginning in early stage HD tissue suggesting abnormal distribution of these proteins. We propose that mutant huntingtin affects proteins involved in synaptic function and cytoskeletal integrity before symptoms develop which may influence early disease onset and/or progression.
DiProspero
Nicholas A
NA
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA. diprospern@ninds.nih.gov
Chen
Er-Yun
EY
Charles
Vinod
V
Plomann
Markus
M
Kordower
Jeffrey H
JH
Tagle
Danilo A
DA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology*; D034281:Dynamins / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009687:Nuclear Proteins; C492182:PACSIN1 protein, human; D014404:Tubulin; C095993:complexin II; D034281:Dynamins