MicroRNA-205 regulates the expression of Parkinson's disease-related leucine-rich repeat kinase 2 protein.

Recent genome-wide association studies indicate that a simple alteration of Leucine-rich repeat kinase 2 (LRRK2) gene expression may contribute to the etiology of sporadic Parkinson's disease (PD). However, the expression and regulation of LRRK2 protein in the sporadic PD brains remain to be determined. Here, we found that the expression of LRRK2 protein was enhanced in the sporadic PD patients using the frontal cortex tissue from a set of 16 PD patients and 7 control samples. In contrast, no significant difference was detected in the level of LRRK2 mRNA expression between the control and PD cases, suggesting a potential post-transcriptional modification of the LRRK2 protein expression in the sporadic PD brains. Indeed, it was identified that microRNA-205 (miR-205) suppressed the expression of LRRK2 protein through a conserved-binding site at the 3'-untranslated region (UTR) of LRRK2 gene. Interestingly, miR-205 expression was significantly downregulated in the brains of patients with sporadic PD, showing the enhanced LRRK2 protein levels. Also, in vitro studies in the cell lines and primary neuron cultures further established the role of miR-205 in modulating the expression of LRRK2 protein. In addition, introduction of miR-205 prevented the neurite outgrowth defects in the neurons expressing a PD-related LRRK2 R1441G mutant. Together, these findings suggest that downregulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD, while overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in PD.

[1]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[2]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[3]  A. Schapira.  Pathogenesis of Parkinson's disease. , 1997, Bailliere's clinical neurology.

[4]  Hailong Wu,et al.  Targeting miR-205 in breast cancer , 2009, Expert opinion on therapeutic targets.

[5]  D. Bartel,et al.  Weak Seed-Pairing Stability and High Target-Site Abundance Decrease the Proficiency of lsy-6 and Other miRNAs , 2011, Nature Structural &Molecular Biology.

[6]  P. Arlotta,et al.  Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum , 2008, The Journal of Neuroscience.

[7]  J. Zhu,et al.  Amyotrophic Lateral Sclerosis 2-Deficiency Leads to Neuronal Degeneration in Amyotrophic Lateral Sclerosis through Altered AMPA Receptor Trafficking , 2006, The Journal of Neuroscience.

[8]  J. Vance,et al.  Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation , 2012, PLoS genetics.

[9]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[10]  Michael J. Devine,et al.  Pathogenic LRRK2 Mutations Do Not Alter Gene Expression in Cell Model Systems or Human Brain Tissue , 2011, PloS one.

[11]  K. Kosik.  The neuronal microRNA system , 2006, Nature Reviews Neuroscience.

[12]  Qunshu Zhang,et al.  Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells , 2010, Cell Death and Disease.

[13]  D. Connor,et al.  The Sun Health Research Institute Brain Donation Program: Description and Eexperience, 1987–2007 , 2007, Cell and Tissue Banking.

[14]  Yusuke Nakamura,et al.  Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease , 2009, Nature Genetics.

[15]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[16]  Heesang Song,et al.  MicroRNA-205 inhibits tumor cell migration through down-regulating the expression of the LDL receptor-related protein 1. , 2009, Biochemical and biophysical research communications.

[17]  R. Burke,et al.  Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease , 2009, Nature Neuroscience.

[18]  I. Ferrer,et al.  Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease , 2011, Journal of Neural Transmission.

[19]  V. Baekelandt,et al.  Distribution of PINK1 and LRRK2 in rat and mouse brain , 2006, Journal of neurochemistry.

[20]  J. Im,et al.  Repression of α-synuclein expression and toxicity by microRNA-7 , 2009, Proceedings of the National Academy of Sciences.

[21]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[22]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[23]  N. Sokol,et al.  Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression , 2010, Nature.

[24]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[25]  Richard H. Myers,et al.  Decreased glutamic acid decarboxylase mRNA expression in prefrontal cortex in Parkinson's disease , 2010, Experimental Neurology.

[26]  H. Shill,et al.  Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction , 2009, Acta Neuropathologica.

[27]  H. Cai,et al.  Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein , 2009, Neuron.

[28]  Ahmet Hoke,et al.  Loss of ALS2 Function Is Insufficient to Trigger Motor Neuron Degeneration in Knock-Out Mice But Predisposes Neurons to Oxidative Stress , 2005, The Journal of Neuroscience.

[29]  H. Cai,et al.  Phosphorylation of Ezrin/Radixin/Moesin Proteins by LRRK2 Promotes the Rearrangement of Actin Cytoskeleton in Neuronal Morphogenesis , 2009, The Journal of Neuroscience.

[30]  B. Giasson,et al.  Mutations in LRRK2 as a Cause of Parkinson’s Disease , 2007, Neurosignals.

[31]  S. Hébert,et al.  Alterations of the microRNA network cause neurodegenerative disease , 2009, Trends in Neurosciences.

[32]  A. Heaford,et al.  Detection of metastatic head and neck squamous cell carcinoma using the relative expression of tissue-specific mir-205. , 2008, Translational oncology.

[33]  M. Byrom,et al.  Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis , 2005, Nucleic acids research.

[34]  D. Nicholl,et al.  Genetics of Parkinson’s disease and parkinsonism , 2007, Expert review of neurotherapeutics.

[35]  J. Holton,et al.  LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study , 2011, Neuropathology and applied neurobiology.

[36]  G. Hannon,et al.  A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons , 2007, Science.

[37]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[38]  O. Sydow,et al.  LRRK2 expression linked to dopamine‐innervated areas , 2006, Annals of neurology.