Global microRNA Expression Profiling of Caenorhabditis elegans Parkinson's Disease Models
- 699 Downloads
MicroRNAs (miRNAs) play an important role in human brain development and maintenance. To search for miRNAs that may be involved in the pathogenesis of Parkinsons disease (PD), we utilized miRNA microarrays to identify potential gene expression changes in 115 annotated miRNAs in PD-associated Caenorhabditis elegans models that either overexpress human A53T α-synuclein or have mutations within the vesicular catecholamine transporter (cat-1) or parkin (pdr-1) ortholog. Here, we show that 12 specific miRNAs are differentially regulated in the animals overexpressing α-synuclein, five in cat-1, and three in the pdr-1 mutants. The family of miR-64 and miR-65 are co-underexpressed in the α-synuclein transgenic and cat-1 strains, and members of let-7 family co-underexpressed in the α-synuclein and pdr-1 strains; mdl-1 and ptc-1 genes are target candidates for miR-64 and miR-65 and are overexpressed in α-synuclein transgenic as well as miR-64/65 (tm3711) knockout animals. These results indicate that miRNAs are differentially expressed in C. elegans PD models and suggest a role for these molecules in disease pathogenesis.
KeywordsmicroRNA Parkinson's disease Neurodegeneration Microarray qRT-PCR Caenorhabditis elegans
We thank the Finnish Graduate School of Neurosciences (FGSN), the Saastamoinen Foundation, and the Sigrid Juselius Foundation for their financial support. This study was supported in part by NIH ES014459 and MHRP W81XWH-05-1-0239 to RN. We thank Petri Pehkonen and Antti Kurronen for advice in computer analysis and Markus Storvik, Vuokko Aarnio, and Julia Vistbakka for fruitful discussions. We thank Dr. Shohei Mitani (Tokyo Women’s Medical University) for providing djr-1.1 and pink-1, and miR-64/65 (tm3711) mutant strains. Some strains used in this study were obtained from the C. elegans Genetics Center, which is funded by the NIH.
SA planned and performed the experiments and wrote the manuscript. MR, LH, KL, JV, and ML performed experiments. GW planned and performed experiments and helped write the manuscript. RN provided critical reagents, guided the study, and helped write the manuscript.
- Liao P, Chen T, Chung P (2001) A fast algorithm for multilevel thresholding. J Info Sci Eng 17:713–727Google Scholar
- Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276(5321):2045–2047CrossRefPubMedGoogle Scholar
- Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J (2003) TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34(2):374–378PubMedGoogle Scholar
- Sawin ER (1996) Genetic and cellular analysis of modulated behaviours in Caenorhabditis elegans. PhD thesis, Massachusetts Institute of TechnologyGoogle Scholar
- Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) A-Synuclein locus triplication causes Parkinson's disease. Science 302(5646):841CrossRefPubMedGoogle Scholar
- Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B (2005) Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of α-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 280:42655–42668CrossRefPubMedGoogle Scholar