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Molecular mechanism underlying the progression of pathology in Parkinson’s disease

On the 19th of December 2014, I defended my PhD-thesis entitled “Molecular mechanism underlying the progression of pathology in Parkinson’s disease”.

Text by Anke Dijkstra

I started to work on my PhD-project in 2008 under supervision of Wilma van de Berg (copromotor), Peter Heutink (promotor) and Henk Groenewegen (promotor) at the department of Anatomy and Neurosciences. I have always been interested in neurodegenerative diseases and my internships focused on Alzheimer’s and Parkinson’s disease in the lab of Peter Heutink and Bart van Berckel (VU University Medical Center).

The main aim of my PhD-thesis was to unravel molecular pathways underlying progression of pathology in Parkinson’s disease. Understanding disease progression and the molecular mechanisms is essential to develop novel neuroprotective or disease-modifying strategies for this devastating disease. To this end, we obtained human post-mortem material from the Netherlands Brain Bank and the department of pathology, VUmc. The pathology of Parkinson’s disease (PD) is characterized by neuronal loss in vulnerable regions in the brain and by the formation of aggregates consisting mainly of misfolded alpha-synuclein, termed Lewy bodies (LBs). These alpha-synuclein aggregates spread throughout the brain in a predictable manner, which is defined in six stages by Braak et al. (2003). We carefully selected donors which may represent the preclinical PD donors with Braak stages 1-3, termed incidental Lewy body disease (iLBD), clinical PD donors with advanced pathology (Braak stages 4-6) and healthy age-matched controls (Braak 0).

Our first goal was to identify if neuronal loss occurs prior to the formation of LBs or in a later stage of the disease. To address this question, we performed neuronal cell counts using the optical fractionator method throughout the substantia nigra (SN). We found that the neuronal loss is present prior to the formation of LBs, indicating that the aggregates might be a secondary event in the pathological cascade in PD. Next, we used the SN tissue from these donors and performed whole-genome transcriptome analysis, which revealed molecular pathways, altered prior to the formation of the LBs and in advanced PD. Interestingly, pathways such as mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 2 (EIF2) signaling were already deregulated in the SN of donors with Braak stages 1 and 2. The alterations in mTOR and EIF2 signaling pathways have also been identified in peripheral mononuclear blood cells transcriptome studies. Influencing these pathways may hold the key to alter disease progression in PD and as alterations in EIF2 are observed in the blood cells, deregulated elements of the EIF2 pathway may serve as biomarkers for PD.

Next, we explored molecular changes in three other vulnerable regions in the brainstem, including olfactory bulb, dorsal motor nucleus of the vagus and locus coeruleus. We found that the immune response, protein synthesis and autophagy are deregulated in all brain regions in iLBD donors. Molecular mechanisms involved in the formation of LBs in all regions in iLBD included the ubiquitin proteasome system (UPS) and mitochondrial dysfunction. In addition, we identified novel pathways in the formation of LBs, including isoleucine and valine degradation and polyamine regulation. Valine and leucine are thought to interact with mTOR and EIF4. Further studies are needed to elucidate the role of these pathways in PD pathology. Wilma van de Berg and Angela Ingrassia are continuing to validate these findings, and follow-up studies based on this data are being conducted in collaboration with Marie-Christine Chartier-Harlin (Lille, France).

Currently, I work as a postdoctoral researcher at the department of Neurology at the University of California, San Francisco, where I study molecular changes in frontotemporal dementia.