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Blood transcriptomics of drug-naïve sporadic Parkinson's disease patients.

Calligaris R, Banica M, Roncaglia P, Robotti E, Finaurini S, Vlachouli C, Antonutti L, Iorio F, Carissimo A, Cattaruzza T, Ceiner A, Lazarevic D, Cucca A, Pangher N, Marengo E, di Bernardo D, Pizzolato G, Gustincich S - BMC Genomics (2015)

Bottom Line: Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes.Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation.It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. calliga@sissa.it.

ABSTRACT

Background: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD.

Methods: Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set").

Results: Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR.

Conclusions: Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus

Drug network analysis. Sub-networks connected to genome-wide ranked lists of genes sorted according to their differential expression in PD: decreasing order in (a) and increasing order in (b), once they are integrated in the drug network as described in Iorio et al. [31]. For clarity we included only the first 35 most similar (resp. “anti-similar”) to PD drugs. Edge thickness is inversely proportional to the distance between the drugs and the conditions. Several antipsychotic drugs (community n. 100 in a) elicit a transcriptional response similar to PD while compounds used for PD treatment elicit an “anti-similar” to PD response (bold in b). The complete list is available in Additional file 14
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Fig3: Drug network analysis. Sub-networks connected to genome-wide ranked lists of genes sorted according to their differential expression in PD: decreasing order in (a) and increasing order in (b), once they are integrated in the drug network as described in Iorio et al. [31]. For clarity we included only the first 35 most similar (resp. “anti-similar”) to PD drugs. Edge thickness is inversely proportional to the distance between the drugs and the conditions. Several antipsychotic drugs (community n. 100 in a) elicit a transcriptional response similar to PD while compounds used for PD treatment elicit an “anti-similar” to PD response (bold in b). The complete list is available in Additional file 14

Mentions: In the search for potential new PD treatments we investigated whether FDA-approved drugs could elicit a transcriptional profile similar or opposite to the one observed in peripheral blood of PD patients. This approach is based on the observation that a large portion of differentially expressed genes in PD blood is expressed in mesencephalic DA neurons and that altered GO biological terms are common in PD blood and post-mortem brains. To this purpose we took advantage of a new approach to identify drug mode of action from gene expression profiles [31]. Specifically, drugs are connected in a network if they elicit a similar transcriptional response according to a new similarity measure based on a modification of GSEA [25]. The drug network consists of 1309 compounds that can be subdivided in 106 communities of drugs, i.e. groups of drugs very similar to each other with a similar mode of action but very different from other drugs in the network. To investigate which drugs trigger the most similar response to the changes found in PD patients, genes were ranked according to their differential expression in PD versus control and the network was queried. The drugs sorted according to their similarity to PD are shown in the Additional file 14. Interestingly, as reported in Fig. 3a, several antipsychotic drugs elicited a transcriptional profile similar to PD (Community 100, P = 3.83x10-6 considering the top-ranked 35 similar to PD drugs and P = 6.76x10-9 considering the top-ranked 100 ones). On the other hand, examining the drugs which elicit an “anti-similar” transcriptional response (i.e. which up-regulate genes found down-regulated in PD and vice-versa), it is noteworthy that apomorphine and levodopa occupy top-ranked positions and are currently used for treating PD (Fig. 3b and Additional file 14).Fig. 3


Blood transcriptomics of drug-naïve sporadic Parkinson's disease patients.

Calligaris R, Banica M, Roncaglia P, Robotti E, Finaurini S, Vlachouli C, Antonutti L, Iorio F, Carissimo A, Cattaruzza T, Ceiner A, Lazarevic D, Cucca A, Pangher N, Marengo E, di Bernardo D, Pizzolato G, Gustincich S - BMC Genomics (2015)

Drug network analysis. Sub-networks connected to genome-wide ranked lists of genes sorted according to their differential expression in PD: decreasing order in (a) and increasing order in (b), once they are integrated in the drug network as described in Iorio et al. [31]. For clarity we included only the first 35 most similar (resp. “anti-similar”) to PD drugs. Edge thickness is inversely proportional to the distance between the drugs and the conditions. Several antipsychotic drugs (community n. 100 in a) elicit a transcriptional response similar to PD while compounds used for PD treatment elicit an “anti-similar” to PD response (bold in b). The complete list is available in Additional file 14
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4625854&req=5

Fig3: Drug network analysis. Sub-networks connected to genome-wide ranked lists of genes sorted according to their differential expression in PD: decreasing order in (a) and increasing order in (b), once they are integrated in the drug network as described in Iorio et al. [31]. For clarity we included only the first 35 most similar (resp. “anti-similar”) to PD drugs. Edge thickness is inversely proportional to the distance between the drugs and the conditions. Several antipsychotic drugs (community n. 100 in a) elicit a transcriptional response similar to PD while compounds used for PD treatment elicit an “anti-similar” to PD response (bold in b). The complete list is available in Additional file 14
Mentions: In the search for potential new PD treatments we investigated whether FDA-approved drugs could elicit a transcriptional profile similar or opposite to the one observed in peripheral blood of PD patients. This approach is based on the observation that a large portion of differentially expressed genes in PD blood is expressed in mesencephalic DA neurons and that altered GO biological terms are common in PD blood and post-mortem brains. To this purpose we took advantage of a new approach to identify drug mode of action from gene expression profiles [31]. Specifically, drugs are connected in a network if they elicit a similar transcriptional response according to a new similarity measure based on a modification of GSEA [25]. The drug network consists of 1309 compounds that can be subdivided in 106 communities of drugs, i.e. groups of drugs very similar to each other with a similar mode of action but very different from other drugs in the network. To investigate which drugs trigger the most similar response to the changes found in PD patients, genes were ranked according to their differential expression in PD versus control and the network was queried. The drugs sorted according to their similarity to PD are shown in the Additional file 14. Interestingly, as reported in Fig. 3a, several antipsychotic drugs elicited a transcriptional profile similar to PD (Community 100, P = 3.83x10-6 considering the top-ranked 35 similar to PD drugs and P = 6.76x10-9 considering the top-ranked 100 ones). On the other hand, examining the drugs which elicit an “anti-similar” transcriptional response (i.e. which up-regulate genes found down-regulated in PD and vice-versa), it is noteworthy that apomorphine and levodopa occupy top-ranked positions and are currently used for treating PD (Fig. 3b and Additional file 14).Fig. 3

Bottom Line: Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes.Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation.It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. calliga@sissa.it.

ABSTRACT

Background: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD.

Methods: Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set").

Results: Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR.

Conclusions: Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus