Microarray Expression Analysis Reveals Genetic Pathways Implicated in C621 Synphilin-1-mediated Toxicity

Overview

Journal J Neural Transm (Vienna)

Specialties Neurology
Physiology

Date 2008 Feb 23

PMID 18292964

Citations 1

Authors

M Bonin

F P Marx

S Kautzmann

O Riess

R Kruger

Affiliations

Soon will be listed here.

Abstract

Synphilin-1 has been linked to Parkinson's disease (PD) based on its role as an alpha-synuclein (PARK1) and Parkin (PARK2) interacting protein and its presence in lewy bodies in brains of PD patients. We recently identified a R621C mutation in the synphilin-1 gene in German PD patients. Functional analyses revealed that mutant synphilin-1 increases cellular stress, however, the involved molecular signalling pathways are currently unknown. Using microarray based gene expression analysis of dopaminergic SH-SY5Y cells overexpressing wild type or R621C mutant synphilin-1 we investigated differentially regulated genes and signalling networks using the Ingenuity Pathways Analysis tool. We show specific effects of C621 mutant synphilin-1 on gene expression that correlate with its role as a susceptibility factor in PD. The most significantly regulated signalling network was defined by the tumor growth factor beta 1 (TGF-beta1) suggesting an involvement of synphilin-1 in TGF-beta mediated signalling pathways modulating the cellular stress response.

Citing Articles

Microarray analysis in a cell death resistant glioma cell line to identify signaling pathways and novel genes controlling resistance and malignancy.

Seznec J, Naumann U Cancers (Basel). 2013; 3(3):2827-43.

PMID: 24212935 PMC: 3759173. DOI: 10.3390/cancers3032827.

References

Flanders K, Ren R, Lippa C . Transforming growth factor-betas in neurodegenerative disease. Prog Neurobiol. 1998; 54(1):71-85. DOI: 10.1016/s0301-0082(97)00066-x. View

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S . Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004; 44(4):601-7. DOI: 10.1016/j.neuron.2004.11.005. View

Oh M, Scoles D, Haipek C, Strand A, Gutmann D, Olson J . Genetic heterogeneity of stably transfected cell lines revealed by expression profiling with oligonucleotide microarrays. J Cell Biochem. 2003; 90(5):1068-78. DOI: 10.1002/jcb.10712. View

Maraganore D, de Andrade M, Elbaz A, Farrer M, Ioannidis J, Kruger R . Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006; 296(6):661-70. DOI: 10.1001/jama.296.6.661. View

Zhang W, Cusack J, Angelo L, Santee S, Fujiwara T, Roth J . Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 1995; 15(6):3032-40. PMC: 230534. DOI: 10.1128/MCB.15.6.3032. View

Wang R, Zhang L, Yin D, Mufson R, Shi Y . Protein kinase C regulates Fas (CD95/APO-1) expression. J Immunol. 1998; 161(5):2201-7. View

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S . Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392(6676):605-8. DOI: 10.1038/33416. View

Valente E, Abou-Sleiman P, Caputo V, Muqit M, Harvey K, Gispert S . Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004; 304(5674):1158-60. DOI: 10.1126/science.1096284. View

Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T . Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease. Neurosci Lett. 1995; 193(2):129-32. DOI: 10.1016/0304-3940(95)11686-q. View

10.

Prehn J, Bindokas V, Jordan J, Galindo M, Ghadge G, Roos R . Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons. Mol Pharmacol. 1996; 49(2):319-28. View

11.

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A . Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276(5321):2045-7. DOI: 10.1126/science.276.5321.2045. View

12.

Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E . The ubiquitin pathway in Parkinson's disease. Nature. 1998; 395(6701):451-2. DOI: 10.1038/26652. View

13.

Maraganore D, Lesnick T, Elbaz A, Chartier-Harlin M, Gasser T, Kruger R . UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol. 2004; 55(4):512-21. DOI: 10.1002/ana.20017. View

14.

Scott W, Nance M, Watts R, Hubble J, Koller W, Lyons K . Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA. 2001; 286(18):2239-44. DOI: 10.1001/jama.286.18.2239. View

15.

Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E . Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2002; 299(5604):256-9. DOI: 10.1126/science.1077209. View

16.

Vawter M, Dillon-Carter O, Tourtellotte W, Carvey P, Freed W . TGFbeta1 and TGFbeta2 concentrations are elevated in Parkinson's disease in ventricular cerebrospinal fluid. Exp Neurol. 1996; 142(2):313-22. DOI: 10.1006/exnr.1996.0200. View

17.

Engelender S, Kaminsky Z, Guo X, Sharp A, Amaravi R, Kleiderlein J . Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet. 1999; 22(1):110-4. DOI: 10.1038/8820. View

18.

Tanaka M, Kim Y, Lee G, Junn E, Iwatsubo T, Mouradian M . Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem. 2003; 279(6):4625-31. DOI: 10.1074/jbc.M310994200. View

19.

Xu P, Liang R, Jankovic J, Hunter C, Zeng Y, Ashizawa T . Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease. Neurology. 2002; 58(6):881-4. DOI: 10.1212/wnl.58.6.881. View

20.

Zetterberg H, Andreasen N, Blennow K . Increased cerebrospinal fluid levels of transforming growth factor-beta1 in Alzheimer's disease. Neurosci Lett. 2004; 367(2):194-6. DOI: 10.1016/j.neulet.2004.06.001. View