Alterations in expression levels of alpha-synuclein and known interactors of alpha-synuclein in Braak 1–2 and PD compared to controls.

<p>Alterations in expression levels of alpha-synuclein and known interactors of alpha-synuclein in Braak 1–2 and PD compared to controls.</p

Schematic overview of molecular processes altered during disease progression in the SN of PD, identified using transcriptome analysis.

<p>In Braak alpha-synuclein 1 and 2, minimal cell loss is observed along with decreased endocytosis and anterograde trafficking, and increased immune response and microglial activation. In addition, we observed down regulation of mRNA levels of the upstream regulators in mTOR pathway. In Braak alpha-synuclein 3 and 4, a steep decline in cell loss and increase in alpha-synuclein pathology is observed together disturbed regulation of protein production and apoptosis of the nigral dopaminergic cells. In Braak alpha-synuclein 5 and 6 compared to controls, severe cell loss and alpha-synuclein aggregation is observed [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128651#pone.0128651.ref041" target="_blank">41</a>]. At this advanced stage, alterations in pathways related to dopaminergic signaling and immune response are still observed.</p

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

<div><p>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.</p></div

Alterations in elements of mTOR, EIF2 and EIF4 signaling pathways in Braak alpha-synuclein 1 and 2 compared to controls.

<p>Image generated using Ingenuity pathway analysis (IPA).</p

Alterations in expression levels of genes involved in endocytosis in the early Braak alpha-synuclein stages 1 and 2 and PD, compared to controls

<p>Alterations in expression levels of genes involved in endocytosis in the early Braak alpha-synuclein stages 1 and 2 and PD, compared to controls</p

Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.

<p>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.</p

Molecular pathways associated with the up- or down-regulated genes in end-stage PD (Braak 5–6) versus controls in our study, compared to other transcriptome studies.

<p>* novel pathways in the SN in PD compared to control</p><p>** BH-FDR<0.05 displayed;</p><p>***Fisher p-value<0.05 displayed</p><p>Molecular pathways associated with the up- or down-regulated genes in end-stage PD (Braak 5–6) versus controls in our study, compared to other transcriptome studies.</p

Ohio History 2011

https://kent-islandora.s3.us-east-2.amazonaws.com/node/10131/OH-v118-thumb.jpgOHIO HISTORY Contents for Volume 118, 2011 Symbolism, Economic Depression, and the Specter of Slavery: William Henry Harrison’s Speaking Tour for the Presidency Jeffrey Bourdon ...... 5 Camp Chase Prison: A Study of Power and Resistance on the Northern Home Front, 1863 Angela M. Zombek ...... 24 The National Cash Register Company and the Neighborhoods: New Perspectives on Relief in the Dayton Flood of 1913 Peter S. Cajka ...... 49 The Boy Who Changed the World: Ohio and the Crippled Children’s Movement Barbara Floyd ...... 72 Toldeo Dentist Charles Betts and the Health Crusade Against Aluminum Jerry Bergman ...... 91 The Origins and Formation of the Latino Community in Northeast Ohio, 1900 to 2009 José O. Solá&nbsp;...... 112 &nbsp; Book Reviews ...... 130 </ul