Parkinson's disease candidate gene prioritization based on expression profile of midbrain dopaminergic neurons

Shahrooz Vahedi,Daniel Grbec,Mehrnoosh Rajabian,Arman Misaghian,Kambiz N Alavian,Horst H Simon

doi:10.1186/1423-0127-17-66

Shahrooz Vahedi, Daniel Grbec + Show 4 more

Open Access

https://doi.org/10.1186/1423-0127-17-66

Copy DOI

Abstract

BackgroundParkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the indentified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes.MethodsIn this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease.ResultsMerging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies.

Highlights

Parkinson’s disease is the second most common neurodegenerative disorder
Two other susceptibility genes, Nurr1 (NR4A2) and tau, which show no linkage to previously described PARK Loci, have been linked to families with Parkinson’s disease [15]
Since five out of seven Parkinson’s disease (PD) genes (a-SYNUCLEIN, PARKIN, UCHL1, PINK1 and Leucine-rich repeat kinase 2 (LRRK2)) plus the two latter genes (NURR1 and TAU) are expressed in midbrain dopaminergic neurons, possibly linking the abnormality in their expression or structure to selective degeneration of substantia nigra pars compacta (SNpc) neurons, expression of genes within this neuronal population seems to be a suitable criterion for narrowing down the number of genes to be further analyzed for identification of PD genes to be associated with orphan PD loci

Summary

Introduction

Parkinson’s disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Based on DNA linkage studies, 13 distinct human chromosomal locations, PARK loci, have been linked to the disease: PARK1 [2], PARK2 [3], PARK3 [4], PARK4 [5], PARK5 [6], PARK6 [7], PARK7 [8], PARK8 [9], PARK9 [10], PARK10 [11], PARK11 [12], PARK12[12], PARK13 [13]. Since five out of seven PD genes (a-SYNUCLEIN, PARKIN, UCHL1, PINK1 and LRRK2) plus the two latter genes (NURR1 and TAU) are expressed in midbrain dopaminergic neurons, possibly linking the abnormality in their expression or structure to selective degeneration of SNpc neurons, expression of genes within this neuronal population seems to be a suitable criterion for narrowing down the number of genes to be further analyzed for identification of PD genes to be associated with orphan PD loci

Methods

Results

Conclusion