Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism.
BACKGROUND
Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood.


OBJECTIVE
To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism.


METHODS
Microarray expression analysis of postmortem substantia nigra tissue.


METHODS
Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects.


METHODS
Identification of genes significantly differentially expressed (P<.05) using Affymetrix U133A microarrays.


RESULTS
There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism.


CONCLUSIONS
Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.
Hauser
Michael A
MA
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. mike.hauser@duke.edu
Li
Yi-Ju
YJ
Xu
Hong
H
Noureddine
Maher A
MA
Shao
Yujun S
YS
Gullans
Steven R
SR
Scherzer
Clemens R
CR
Jensen
Roderick V
RV
McLaurin
Adam C
AC
Gibson
Jason R
JR
Scott
Burton L
BL
Jewett
Rita M
RM
Stenger
Judith E
JE
Schmechel
Donald E
DE
Hulette
Christine M
CM
Vance
Jeffery M
JM
D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology*; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000473:pathology