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.
Hodges
Angela
A
Department of Psychological Medicine, Wales College of Medicine and School of Biosciences, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK.
Strand
Andrew D
AD
Aragaki
Aaron K
AK
Kuhn
Alexandre
A
Sengstag
Thierry
T
Hughes
Gareth
G
Elliston
Lyn A
LA
Hartog
Cathy
C
Goldstein
Darlene R
DR
Thu
Doris
D
Hollingsworth
Zane R
ZR
Collin
Francois
F
Synek
Beth
B
Holmans
Peter A
PA
Young
Anne B
AB
Wexler
Nancy S
NS
Delorenzi
Mauro
M
Kooperberg
Charles
C
Augood
Sarah J
SJ
Faull
Richard L M
RL
Olson
James M
JM
Jones
Lesley
L
Luthi-Carter
Ruth
R
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