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DNA Research Advance Access published online on May 23, 2007
DNA Research, doi:10.1093/dnares/dsm007
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© The Author 2007. Kazusa DNA Research Institute
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Merging Mouse Transcriptome Analyses with Parkinson's Disease Linkage Studies

Daniel Gherbassi, Lavinia Bhatt, Sandrine Thuret {dagger} and Horst H. Simon*

Department of Neuroanatomy, Interdisciplinary Center for Neuroscience, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany

Received 5 September 2006; revised 26 March 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Supplementary Data
 Acknowledgements
 References
 
The hallmark of Parkinson's disease (PD OMIM #168600) is the degeneration of the nigral dopaminergic system affecting approximately 1% of the human population older than 65. In pursuit of genetic factors contributing to PD, linkage and association studies identified several susceptibility genes. The majority of these genes are expressed by the dopamine-producing neurons in the substantia nigra. We, therefore, propose expression by these neurons as a selection criterion, to narrow down, in a rational manner, the number of candidate genes in orphan PD loci, where no mutation has been associated thus far. We determined the corresponding human chromosome locations of 1435 murine cDNA fragments obtained from murine expression analyses of nigral dopaminergic neurons and combined these data with human linkage studies. These fragments represent 19 genes within orphan OMIM PD loci. We used the same approach for independent association studies and determined the genes in neighborhood to the peaks with the highest LOD score value. Our approach did not make any assumptions about disease mechanisms, but it, nevertheless, revealed {alpha}-synuclein, NR4A2 (Nurr1), and the tau genes, which had previously been associated to PD. Furthermore, our transcriptome analysis identified several classes of candidate genes for PD mutations and may also provide insight into the molecular pathways active in nigral dopaminergic neurons.

Key words: dopaminergic neurons; substantia nigra; neurodegenerative disease; candidate genes


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 Supplementary Data
 Acknowledgements
 References
 
The neuropathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), affecting about 1–2% of the human population older than 65 years.1Go It is characterized by the clinical symptoms of resting tremor, muscular rigidity, postural instability, a positive response to the administration of L-DOPA, and the presence of cytoplasmic inclusions in postmortem brains, Lewy Bodies.2Go Despite its mostly sporadic onset and a high discordance rate in monozygotic twins,3Go several human linkage studies had been initiated to determine susceptibility genes for this disease.4Go In the Online Mendelian Inheritance in Man (OMIM) database, 13 PD loci have been recorded: PARK1,5Go PARK2,6Go–9Go PARK3,10Go PARK4,11Go,12Go PARK5,13Go PARK6,14Go,15Go PARK7,16Go,17Go PARK8,18Go PARK9,19Go,20Go PARK10,21Go PARK11,22Go,23Go PaRK12,23Go,24Go and PARK13.25Go Furthermore, genome-wide analyses of multiplex PD families provided evidence for linkage to regions on different chromosomes.21Go,22Go,24Go,26Go–29Go The PARK loci are sometimes larger than 10 Mb and can contain hundreds of genes. In case of the genome-wide linkage studies for a complex, multifactorial disease such as PD, the regions with high LOD scores are rarely smaller than 20 cM.29Go The differences among independent studies and the size of the suggested susceptibility regions make the searches for the underlying mutations irremediably a time-consuming process.

For several PARK loci, the searches have been successful. Mutations in {alpha}-synuclein (PARK1 and PARK4), DJ-1 (PARK7), parkin (PARK2), PINK1 (PTEN-induced putative kinase) (PARK6), LRRK2 (leucine-rich repeat kinase 2) (PARK8), UCHL1 (ubiquitin carboxy-terminal-hydrolase-L1) (PARK5), and ATP13A2 (ATPase type 13A2) (PARK9) have been identified.5Go,30Go–37Go Other studies have revealed the cytoskeletal protein tau (MAPT)36Go,38Go and the ligand-independent nuclear receptor NR4A230Go,39Go,40Go (Nurr1) as susceptibility genes. Although the definite role in PD of many of these genes is still discussed and controversial (especially for NR4A2 and UCHL1) and the known mutations account for less than 10% of all PD cases, the investigation into the functions of the underlying genes has generated an insight into the fundamental disease pathogenesis. For example, {alpha}-synuclein and parkin turned out to be major protein components of Lewy bodies in sporadic PD.41Go Mutations in parkin, UCHL1, and DJ-1 suggest that abnormal protein folding and protein degradation through the ubiquitin-proteasome system is an important factor in the etiology of the disease.42Go,43Go PINK1 may be involved in the phosphorylation of mitochondrial proteins in response to cellular stress, thus protecting against mitochondrial dysfunction.35Go Interestingly, mitochondria are also the site, where the known neurotoxins for DA neurons operate, suggesting that their malfunctioning could be a major contributor to PD pathogenesis.44Go

Current or future searches for the underlying mutations in the remaining orphan Parkinson loci could be accelerated and widened to promoter regions and to haplotype variations, if the number of candidate genes is narrowed down by other criteria. At least seven out of the nine PD-associated genes are expressed by nigral DA neurons,45Go–50Go with different expression levels and specificity. These are {alpha}-synuclein, NR4A2, parkin,46Go PINK1, tau, UCHL1, and LRRK1 (http://www.brain-map.org). For this reason, we propose expression (specific or non-specific) by mesDA neurons as a selection criterion to identify candidate genes in those PD loci where the underlying gene is still unknown (orphan). Such an approach does not make any presumption with respect to disease mechanisms. Conceptually, the same method was applied on five large PD loci using serial analysis of gene expression for a comparative expression analysis of SNpc and adjacent mesencephalon in postmortem brains.51Go As cell-specific expression in mouse and human is very similar, we took three murine expression studies which employed fluorescent-activated cell sorting (FACS) and two unrelated subtractive methods for the identification of genes expressed by mesDA neurons.52Go–54Go We collected the cDNA sequences of these expression analyses from public databases, determined the underlying genes and the corresponding gene ontology annotations [Gene Ontology (GO)] to obtain insight into their function. Then, we established their genetic locations and their syntenic positions on the human genome. Finally, we combined these data with existing human PD linkage studies.5Go–11Go,13Go–24Go,26Go–29Go,55Go,56Go


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 Supplementary Data
 Acknowledgements
 References
 
2.1. Transcriptome analysis
All nucleotide sequences used in this study are publicly available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide and derived from three expression analyses in mouse: (i) Barrett et al.52Go published 779 sequences (Accession Nos.: BE824469 [GenBank] –BE824504 [GenBank] , BE824506 [GenBank] –BE824519 [GenBank] , BE824521 [GenBank] –BE824561 [GenBank] , BE824563 [GenBank] –BE824823 [GenBank] , BE824825 [GenBank] –BE825045 [GenBank] , BE825047 [GenBank] –BE825132 [GenBank] , CK338036 [GenBank] –CK338155 [GenBank] ). (ii) Stewart et al.53Go,57Go,58Go published 496 cDNA sequences (Accession Nos.: AA008736 [GenBank] , W33210 [GenBank] –W33212, W33214 [GenBank] –W33289, W35421 [GenBank] –W35480, W36130 [GenBank] –W36269, W39787 [GenBank] –W40005, W40007 [GenBank] –W40008, W40010 [GenBank] –W40023, W45732 [GenBank] ). (iii) We published 160 sequences (Accession Nos.: CO436137 [GenBank] –CO436293 [GenBank] ).54Go

Each nucleotide sequence was employed for a nucleotide-nucleotide BLAST (blastn) (basic local alignment search tool) on the nr database (non-redundant) (http://www.ncbi.nlm.nih.gov/BLAST/) and on the mouse genome (http://www.ncbi.nlm.nih.gov/genome/seq/MmBlast.html). We then recorded those alignments with the highest scores, the lowest e-values, and highest number of hits in a single locus. BLAST results were categorized into four groups: (1Go) no significant alignments on mouse genome (None), (2Go) significant alignments with mitochondrial DNA (Mitochondrial Genes), (3Go) multiple high-scoring alignments on mouse genome (Multiple Hits) for ambiguous results, and (4Go) significant alignments on mouse genome for single hits or otherwise unambiguous results (Table 1). The latter group was further subdivided into: ‘Genes’, ‘ESTs’, and ‘genomic Sequences’. The group ‘Genes’ comprises the results with high-scoring alignments in exons of single genes. In some cases, where the alignment lay in the region after the last exon or, according to the chromosome map view, in an intron of a given gene, we termed it also ‘Gene’, if the hit was in a UniGene cluster which was linked to the gene in the locus. With those alignments that we were unable to associate to a gene, we performed a blastn on the MmEST database. If we could associate the sequence to a previously described EST, we termed it ‘EST’; otherwise, it was termed ‘Genomic Sequence’.


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  		Table 1.. BLAST results on mouse genome

 
For all the ‘Annotated Genes’, ‘Hypothetical Genes’, and mitochondrial genes, the following data were collected from the locus link feature (http://www.ncbi.nlm.nih.gov/LocusLink this was replaced by http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene during the course of this study): the gene name, gene symbol, accession number, Gene ID, and the MGI link number, if available. The latter provides a relational link to the GO library and the information related to ‘biological processes’, ‘cellular components’, and ‘molecular functions’.

For all cDNA sequences categorized by ‘Significant Alignments on Mouse Genome’, we also registered the exact chromosomal position in kilobases (starting from the top of the short arm).

2.2. Mapping the murine cDNA sequences to the human genome
For most of the murine genes, a human homolog has already been determined, normally carrying the same name and symbol. This information is registered on the Entrez Gene page together with the cytogenetic locations. When this information did not exist, we used the mouse protein sequence of the identified gene for a translated BLAST (tblastn), or the nucleotide sequence of the cDNA fragment or the GenBank accession number of the corresponding gene for a blastn on the human genome. We registered the position in kilobases on the chromosome and verified each position on the human genome by comparing the neighboring genes to those in the mouse genome and recorded the human position only if the neighboring genes also matched.

When the cytogenetic position on the human genome was determined, we compared this information with the positions of the recorded PARK loci. We aligned the human chromosome map view with the map for ‘morbid/disease’, described in OMIM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM). When the genes, or the estimated human locations, and the cytogenetic disease locations co-localized, we called the gene a PD candidate gene. For the loci suggested by genome-wide studies, we selected those genes, which were situated ±3 Mb from the chromosome marker (single nucleotide polymorphism (SNP)) with the highest LOD score (Table. 5). We are aware that this approach reduces the numbers of genes in an arbitrary manner. However, if preferred, the range can be widened with the provided data (see Supplementary Data) in order to more accurately consider asymmetry or size of each specific linkage peak.

The entire data set was collected and processed using the database program, Filemaker Pro 7.0. The latest update was in February 2007. This database is available upon request.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 Supplementary Data
 Acknowledgements
 References
 
We obtained 1435 sequences from three independent studies, which had the original aim to identify genes expressed by mesDA neurons. Barrett et al.52Go had isolated DA neurons from E13 ventral midbrain by FACS. This library contains genes expressed by mesDA neurons with a preference for abundant genes. The other two studies used subtractive methods to enrich for rare RNA transcripts expressed by mesDA neurons. Stewart et al.53Go,57Go,58Go had created a single-stranded directional cDNA library from substantia nigra of 8-week-old mice subtracted with a cDNA library from cerebellum. We had used a PCR-based differential display method54Go employing cDNA from engrailed-1/2 double-mutant and wild-type ventral midbrain during the embryonic stages when mesDA neurons disappear in the mutants.59Go,60Go The amplified sequences were compared to the expression profile of adult olfactory bulb, a source of DA neurons unrelated to those in the ventral midbrain. Only differentially expressed cDNA fragments were isolated and sequenced. As the original sequence analyses of the former two studies had been performed when a smaller nucleotide data set was available and in order to update our own expression analysis, we subjected the sequence data from all three screens to new BLAST searches and determined their association to genes and published ESTs, and their location on the mouse genome. The 1435 cDNA fragments generated 1050 unambiguous murine genomic hits, 19 ambiguous multiple hits, and 104 alignments with mitochondrial DNA. Two hundred and sixty-two cDNA sequences produced no significant alignments (see Table 1 for definitions and the entire analysis, and Table 2 for the individual libraries).


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  		Table 2.. Classification of BLAST results from each library

 
Out of 1050 cDNA fragments, which generated unambiguous alignments on the mouse genome, 1020 were in gene loci. Most of them aligned to exons of those genes (72.6%; 741 of 1020). Out these 1020 cDNA fragments, 181 (17.8%) lay 3' to the last annotated exon, suggesting that substantial amounts of mRNAs isolated from brain tissue are longer at their 3' end than mRNAs from other tissues (Table 3). Finally, 9.6% (98 of 1020) of the alignments lay in regions designated as introns, suggesting that they are parts of unrecorded splice variants, possibly specific for mesDA neurons.


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  		Table 3.. Alignments in relation to gene loci

 
The 1050 cDNA fragments represented 503 genes (423 annotated and 80 hypothetical genes), 32 ESTs, and 44 unique genomic hits with no otherwise described ESTs. Additionally, the 104 sequences that aligned to the mitochondrial DNA represented 11 mitochondrial genes (Table 2). To these cDNA sequences, we associated the corresponding MGI numbers, if available. This provided us with insight into their molecular function, the cellular locations of the proteins, and the associated biological process (see Supplementary Data for the entire transcriptome analysis). Several protein classes were over-represented, like, for example, those, which take part in mitochondria-related processes, in fatty acid chain metabolism, in ubiquitination, in the MAPK signaling pathways, or which are chaperones. Some of these molecular pathways were previously linked to the death of mesDA neurons, to PD, and other human neurodegenerative disorders.

The majority of the mutations, which are associated to PD, is in genes that are expressed in mesDA neurons. We, therefore, joined these expression analyses with human PD linkage and association studies,5Go–11Go,13Go–24Go,26Go–29Go,55Go,56Go where no mutation has been associated thus far. For each unique mouse cDNA sequencing tag, we determined its human homolog and the corresponding cytogenetic and physical positions on the human chromosomes. We verified each locus on the human genome by identifying the neighboring genes on the mouse genome and recorded the human position only if the adjacent genes were the same. We then determined whether these positions were within OMIM (Table 4) and other suggestive (non-OMIM) PD loci (Table 5). In case of the OMIM orphan PD loci, we projected on the human chromosome view the map for ‘morbid diseases’. In case of non-OMIM loci, we identified the genes ±3 Mb to the SNP marker with the highest LOD score. Totally, we linked the mouse transcriptome analyses to 569 unique locations on the human genome. Nineteen of these are within orphan PARK loci (Table 6) and 51 in non-OMIM PD loci (Table 7).


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  		Table 4.. PARK loci

 


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  		Table 5.. Association studies not recorded at OMIM

 


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  		Table 6.. Candidate genes in Orphan PARK loci

 


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  		Table 7.. Candidate genes for non-OMIM PARK loci

 
The experimental design of the three different transcriptome analyses, we used for our study, were such that they included both highly and rarely expressed transcripts. Our analysis confirmed the complementary nature of the three screens. Only 7.2% (104 out of 1435) of the cDNA sequences of these libraries represent genes, hypothetical genes, or EST clusters, which are found in more than one of them (Table 8). Moreover, the libraries also contained two cDNA fragments for {alpha}-synuclein, three for NR4A2, and one for the tau genes. Mutations in all three genes have been previously associated to PD.5Go,30Go,36Go Assuming that all 30 000 genes in the human genome61Go were equally likely detected, the probability to identify three of nine PD susceptibility genes by chance out of a pool of 569 was less than 3.4 x 10–3. If we exclude the controversial NR4A2 and UCHL1, the probability was less than 1.5 x 10–2.


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  		Table 8.. cDNA library comparison

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
Supplementary Data
 Acknowledgements
 References
 
The entire human and mouse genome sequences have been available for more than 3 years.61Go,62Go Therefore, the chromosomal locations of most genes have been determined and as a consequence also those genes within a given disease locus. In order to identify potential PD susceptibility genes, we projected the sequence data of three murine transcriptome studies for mesDA neurons onto the human genome and compared them with previously identified PD loci. We determine the human homologs of 1435 murine cDNA fragments which corresponded to 579 unique mouse chromosomal locations; 423 annotated genes, 80 hypothetical genes, 32 ESTs, and 44 genomic locations, which are not linked to any genes or otherwise reported cDNA sequences. Of the 569 unique locations on the human genome, 19 were positioned in OMIM PARK loci and 51 within genomic regions that have a weaker linkage to PD, which are not recorded in the OMIM database and need further confirmation.

Multiple studies are on the way to determine the underlying mutations of orphan PARK loci63Go; however, the length of putative regulatory regions of most gene, their unpredictable position, and the common presence of SNPs have thus far restricted such studies to nucleotide variation in the coding region and in 5' and 3' UTR. Disparities in the promoter–enhancer–silencer regions were only the aim if the targeted gene had been previously linked to PD.64Go,65Go A nucleotide variation in the {alpha}-synuclein promoter, for example, was associated to the disease.12Go,66Go Variability on the level of gene expression is far more common than nucleotide variations which alter protein sequences67Go and it is believed that these haplotype variations determine individual traits and predispositions for common diseases such as PD. Narrowing down the number of candidate genes in identified loci in a rational manner may encourage the inclusion of the promoter regions in future studies aiming to identify mutations associated to PD.

Among the candidate genes that we found, the most interesting is VMAT2 (vesicular monoamine transporter 2) (10q25). Reduced expression of VMAT2 could be correlated with a higher sensitivity to environmental factors. For example, VMAT2 heterozygote mice (+/ – ) are remarkably more sensitive than wild-type to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.68Go,69Go Furthermore, we identified two genes in the ubiquitination pathway, Ube2b [ubiquitin-conjugating enzyme E2B, RAD6 homology (S. cerevisiae)] and Ubb (Ubiquitin B, member of the HSP90 family) and Hspa5 (heat shock 70 kDa protein 5, member of the HSP70 family).

Finally, 26 mitochondrial genes encoded by nuclear DNA are present in our transcriptome analysis. Of these, an unexpected high proportion of genes, namely four, are located within orphan OMIM PARK loci. There is increasing evidence that impairment of mitochondrial functions and oxidative stress are contributing factors to PD70Go supported by the recent finding of a mutation in PINK1.35Go Furthermore, the functional deficiencies induced by several of the other PD mutations seem to converge onto the mitochondria.71Go Our finding confirms a central role of the mitochondria in PD and suggests the possibility that a misregulation of some of these four mitochondrial genes may be a contributing factor for the disease.

We conclude that our transcriptome analysis, along with being applicable for the identification of PD candidate genes, may also be a useful tool for future genome-wide association studies with newer resources, such as HapMap (http://www.hapmap.org/), where tagSNPs can be chosen close to loci of genes expressed by mesDA neurons. Furthermore, new GO annotations are constantly added and with time it may turn out that many of the identified genes are part of shared metabolic pathways. Our data set may give new insight into ligand/receptor interactions and/or intracellular signaling pathways acting in mesDA neurons, allowing novel studies into the molecular etiology of PD.


   Supplementary Data
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Supplementary Data
Acknowledgements
 References
 
Supplementary data are available online at www.dnaresearch.oxfordjournals.org.


   Acknowledgements
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Supplementary Data
 Acknowledgements
References
 
This work was supported by a grant from the German Federal Secretary for Education and Research (BMBF) Biofuture 98.


   Footnotes
 
* To whom correspondence should be addressed. Tel. +49-6221-548342. Fax. +49-6221-545605. E-mail: horst.simon{at}urz.uni-heidelberg.de

Communicated by Shoji Tsuji

{dagger} Present address: King's College London, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, P039, 1-2 WW Ground, Denmark Hill, London SE5 8AF, UK. Back


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Supplementary Data
 Acknowledgements
 References
 

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