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Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson's Disease.

Dijkstra AA, Ingrassia A, de Menezes RX, van Kesteren RE, Rozemuller AJ, Heutink P, van de Berg WD - PLoS ONE (2015)

Bottom Line: Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN.Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression.These pathways may hold the key to altering the disease progression in PD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurosciences, section Quantitative Morphology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands; Department of Medical genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson's disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0-6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.

No MeSH data available.


Related in: MedlinePlus

Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.Red is control, blue is iLBD and green is PD donor. The two main clusters are formed by 1) controls and iLBD and 2) PD and iLBD, indicating that the expression of iLBD is intermediate between control and PD. Seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.
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pone.0128651.g001: Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.Red is control, blue is iLBD and green is PD donor. The two main clusters are formed by 1) controls and iLBD and 2) PD and iLBD, indicating that the expression of iLBD is intermediate between control and PD. Seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.

Mentions: In order to identify differences in genome wide gene expression patterns between PD, iLBD and controls, we performed microarray analysis of the SN. First, an unbiased hierarchical cluster analysis was applied to the microarray dataset to study the clustering of the gene expression data of the 3 pathological groups (Fig 1). Within the cluster, there was full separation between PD and control samples, indicating substantial differences in gene expression profiles. The expression profiles of the iLBD subjects clustered either together with the control cases, or with the PD, but they didn’t form their own cluster, indicating that their expression levels are intermediate between control and PD gene expression profiles. Unexpectedly, seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.


Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson's Disease.

Dijkstra AA, Ingrassia A, de Menezes RX, van Kesteren RE, Rozemuller AJ, Heutink P, van de Berg WD - PLoS ONE (2015)

Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.Red is control, blue is iLBD and green is PD donor. The two main clusters are formed by 1) controls and iLBD and 2) PD and iLBD, indicating that the expression of iLBD is intermediate between control and PD. Seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472235&req=5

pone.0128651.g001: Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.Red is control, blue is iLBD and green is PD donor. The two main clusters are formed by 1) controls and iLBD and 2) PD and iLBD, indicating that the expression of iLBD is intermediate between control and PD. Seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.
Mentions: In order to identify differences in genome wide gene expression patterns between PD, iLBD and controls, we performed microarray analysis of the SN. First, an unbiased hierarchical cluster analysis was applied to the microarray dataset to study the clustering of the gene expression data of the 3 pathological groups (Fig 1). Within the cluster, there was full separation between PD and control samples, indicating substantial differences in gene expression profiles. The expression profiles of the iLBD subjects clustered either together with the control cases, or with the PD, but they didn’t form their own cluster, indicating that their expression levels are intermediate between control and PD gene expression profiles. Unexpectedly, seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.

Bottom Line: Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN.Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression.These pathways may hold the key to altering the disease progression in PD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurosciences, section Quantitative Morphology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands; Department of Medical genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson's disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0-6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.

No MeSH data available.


Related in: MedlinePlus