sgk1, a member of an RNA cluster associated with cell death in a model of Parkinson's disease.
In an effort to gain deeper insight into the molecular processes underlying neurodegeneration in Parkinson's disease, we performed gene expression profiling at several early time points after MPTP-injection into old (1-year) mice. We used a PCR-based gene expression profiling method, digital expression pattern display (DEPD), a method of very high sensitivity and reproducibility, which displays almost all transcripts of a tissue. To identify cell death-associated genes, we defined clusters of differentially expressed transcripts with expression behaviour that correlated with the temporal profile of cell death progression and characterized one of these cell death clusters further. We selected one of the strongest regulated genes, the serum and glucocorticoid-regulated kinase 1 (sgk1), and validated its differential expression by Northern blot analysis, semiquantitative PCR and in situ hybridization. Up-regulation of sgk1 (i) coincides with the onset of dopaminergic cell death in both the 8-week acute and 1-year subacute MPTP models, (ii) spans the entire brain, (iii) is attenuated by the l-deprenyl-mediated inhibition of the MPTP conversion to its active metabolite MPP+ and (iv) is not induced by dehydration. This study demonstrated that the combination of the DEPD technology, clustering analysis and a detailed histopathology is a useful tool for elucidating molecular pathways in neurodegenerative diseases.
Stichel
Christine C
CC
Biofrontera Pharmaceuticals GmbH, D-51377 Leverkusen, Germany. c.stichel-gunkel@biofrontera.com
Schoenebeck
Bodo
B
Foguet
Montserrat
M
Siebertz
Barbara
B
Bader
Verian
V
Zhu
Xin Ran
XR
Lübbert
Hermann
H
D000367:Age Factors; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004347:Drug Interactions; D005508:Food Deprivation; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012642:Selegiline / Q000008:administration & dosage; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014868:Water Deprivation; D000099184:Serum-Glucocorticoid Regulated Kinases
D000978:Antiparkinson Agents; D005904:Glial Fibrillary Acidic Protein; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012642:Selegiline; D014446:Tyrosine 3-Monooxygenase; D000099184:Serum-Glucocorticoid Regulated Kinases