Regional and cellular gene expression changes in human Huntington's disease brain.
Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
Department of Psychological Medicine, Wales College of Medicine and School of Biosciences, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK.
Angela
A
Hodges
Andrew D
AD
Strand
Aaron K
AK
Aragaki
Alexandre
A
Kuhn
Thierry
T
Sengstag
Gareth
G
Hughes
Lyn A
LA
Elliston
Cathy
C
Hartog
Darlene R
DR
Goldstein
Doris
D
Thu
Zane R
ZR
Hollingsworth
Francois
F
Collin
Beth
B
Synek
Peter A
PA
Holmans
Anne B
AB
Young
Nancy S
NS
Wexler
Mauro
M
Delorenzi
Charles
C
Kooperberg
Sarah J
SJ
Augood
Richard L M
RL
Faull
James M
JM
Olson
Lesley
L
Jones
Ruth
R
Luthi-Carter
D000328:Adult; D000368:Aged; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics
D012333:RNA, Messenger