Project II. Long Noncoding RNAs as Epigenomic Modulators and CSF Biomarkers in Parkinson's Disease This proposal will explore the presence and differential expression of non-protein-coding RNAs (ncRNAs) in cerebrospinal fluid (CSF) and tissue samples from patients with Parkinson's disease (PD) and their relationship to the methylation status of the protein coding genes they regulate. In addition, this project will aim to develop biomarker panels in order to diagnose PD, monitor disease progression and response to treatment. The mammalian genome is subject to a vast array of transcriptional events, generating a wide spectrum of functional RNA species. These molecules range from the familiar protein-coding mRNAs to long non-coding transcripts whose diversity appears to match that of mRNAs. We hypothesize that the ncRNAs are deeply involved in PD pathophysiology, through induction of epigenetic modifications. NcRNAs may be proven helpful to explain the causes, to define novel therapeutic targets and to delineate biomarkers for PD. We will harness the power of sequencing technologies to discover novel RNAs involved in PD, in order to shed light on pathological processes and provide a basis for improved diagnosis and patient care. Recent publications have revealed an important role for dysregulation of ncRNAs in various human neuropathologies, such as Alzheimer's disease [1, 2], PD [3] and Fragile X mental retardation [4]. Our study will allow the discovery of novel ncRNAs in the CSF and brain of PD subjects and define the mechanistic role these ncRNAs play in the modification of epigenetic marks, such as CpG methylation. We will examine the RNA and protein content of CSF from PD subjects for biomarker evidence of these epigenetic changes. We strongly believe that we will be able to describe the genome wide effects of ncRNAs expression on methylation status and tie this to a practical and measurable biomarker.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071674-05
Application #
8740568
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
5
Fiscal Year
2014
Total Cost
$500,421
Indirect Cost
$173,348
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Alcalay, Roy N; Caccappolo, Elise; Mejia-Santana, Helen et al. (2014) Cognitive and motor function in long-duration PARKIN-associated Parkinson disease. JAMA Neurol 71:62-7
Nuytemans, Karen; Inchausti, Vanessa; Beecham, Gary W et al. (2014) Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease. Mov Disord 29:827-30
Nalls, Mike A; Pankratz, Nathan; Lill, Christina M et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46:989-93
Huang, Anhui; Martin, Eden R; Vance, Jeffery M et al. (2014) Detecting genetic interactions in pathway-based genome-wide association studies. Genet Epidemiol 38:300-9
Wang, Liyong; Nuytemans, Karen; Bademci, Guney et al. (2013) High-resolution survey in familial Parkinson disease genes reveals multiple independent copy number variation events in PARK2. Hum Mutat 34:1071-4
Nuytemans, Karen; Bademci, Guney; Inchausti, Vanessa et al. (2013) Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 80:982-9
Hedges, Dale J; Guettouche, Toumy; Yang, Shan et al. (2011) Comparison of three targeted enrichment strategies on the SOLiD sequencing platform. PLoS One 6:e18595
Williams, Sion L; Huang, Jia; Edwards, Yvonne J K et al. (2010) The mtDNA mutation spectrum of the progeroid Polg mutator mouse includes abundant control region multimers. Cell Metab 12:675-82