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Delineating the Synaptosome Signaling Network in Parkinson's Disease

This research project aims to investigate the synaptosome signaling network involved in the progression of Parkinson's disease and its impact on learning and memory. The study will utilize proteomics and phosphoproteomics analysis to elucidate the dysregulation of synaptic function and identify potential therapeutic targets. Animal models will be utilized to validate the findings. The outcome of this research will contribute to a better understanding of the disease and aid in developing novel treatment strategies.

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Delineating the Synaptosome Signaling Network in Parkinson's Disease

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  1. Delineating the synaptosome signaling network of learning and memory in the progression of Parkinson’s disease Funding Agency DST- SERB (Individual centric) Project venue: YU-IOB, CSBMM YRC, Yenepoya University

  2. Investigator details • Principal Investigator: Dr. PrashantModi, Senior Scientific Officer, YU-IOB CSBMM, YRC • Co-Investogators • Dr. KeshavaPrasad, Deputy Director, YU-IOB CSBMM, YRC • Dr. SnehaPinto, DST-INSPIRE Faculty,YU-IOB CSBMM, YRC • Dr. YashwanthSubbannaya, Asst. Prof, YU-IOB CSBMM, YRC

  3. Introduction • Parkinson’s disease is a widely prevalent progressive neurodegenerative disease of the elderly • The most prescribed medicine for management of PD is Levodopa, a dopamine precursor and other medications include dopamine agonists (Pramipexole and Ropinirole) and Monoamine Oxidase-B type (MAO-B) inhibitors (Selegiline and Rasagiline) • The neurotransmitter dopamine is very closely related to learning and motivation, which is why there is a progressive loss of both in PD. This link was well established when human subjects with PD failed to show improvement in learning and motivation

  4. Synaptosome • A synaptosome is derived from synaptic terminals, isolated from the rest of the neuronal cell body • It contains the pre- and post- synaptic terminal, the synaptosomal mitochondria, synaptic vesicles, and postsynaptic density Fig. 2 Electronmicrograph of Synaptosome Fig. 1 Representation of Synaptosome https://www.thermofisher.com/content/dam/LifeTech/Images/integration/A12n03-Fig1-87793-Syn-PER.jpg FengjuBaiand Frank A. Witzmann, 2007

  5. Research status

  6. continued

  7. Research statusSynaptosomes in diseases • Synaptic dysfunction in a number of neurological diseases including Alzheimer’s disease (AD), Parkinson’s disease and Schizophrenia (Jhou, 2017) • A number of studies on synaptosomes has concentrated on AD than any other neurological disorder • proteins like tau, amyloid-β precursor has been reported in the synaptosome(Tai, 2012; Fein, 2008) • Proteomic profiling of the synaptosomes and the post-synaptic density has been carried out to reveal the synaptosomal networks in mice model of schizophrenia (20)

  8. Lacunae • No study on global proteomic and phosphoproteomic study on PD • Synaptosomal mitochondrial dysregulation has been observed in learning and memory • The synaptosome proteomic profiling in the progression of Parkinson’s disease, with respect to learning and memory has not been elucidated

  9. Hypothesis The synaptosomal signaling involved in learning and memory, are dysregulated during the progression of Parkinson’s disease

  10. Proposed Aim To delineate the synaptosome signaling network of learning and memory in the progression of Parkinson’s disease

  11. Proposed Objectives • To establish the PD rat model using MPTP and assess their learning and memory functions • To isolate the synaptosomes from the rat brain from striatum, SNpc and hippocampus • To carry out mass spectrometry based proteomics and phophoproteomics analysis • To validatethesynaptosome network using Co-IP • To develop a synaptosome network for Parkinson’s disease and normal rat

  12. Ethical issues • Animal studies will be carried out to understand the synaptosomal signaling • Institutional Animal Ethics Committee approval will be soughted

  13. Proposed Work Flow

  14. Proposed Methodology • Wistar Rats- MPTP model of PD (mitochondrial dysregulation model) • Assessment of learning and memory (novel objects, Barnes maze) • Synaptosome isolation from substantianigra, striatum, hippocampus, amgdala • Sample preparation for global proteomics and phosphopeptide enrichment • LC-MS/MS analysis (liquid chromatography- mass spectrometery) • Bioinformatics based network analysis • Validation of protein interactions using Co-IP based MS analysis and western blotting

  15. Proposed Time line

  16. Proposed Budget

  17. Expected outcome • Protein interaction networks, involved in learning and memory of PD • Alterations in the protein interactome of PD and control cases

  18. Benefits of the research proposal • The research outcome from the project will enable us to understand the dynamics involved in the synaptosomal vesicle formation and the alterations in the mechanism, in case of Parkinsonism • The understanding of the synaptosomal network in animal model can thus be extrapolated to delineate the pathways in human and thereby identification of novel targets that can be manipulated for progressive outcomes in the management of the disease

  19. Reference Collins MO, Yu L, et al. Robust enrichment of phosphorylated species in complex mixtures by sequential protein and peptide metal-affinity chromatography and analysis by tandem mass spectrometry. Sci STKE 2005b;2005:16. Coughenour HD, Spaulding RS, et al. The synaptic vesicle proteome: a comparative study in membrane protein identification. Proteomics 2004;4:3141–3155. [PubMed: 15378707]Hansson E, Ronnback L. Glial neuronal signaling in the central nervous system. FASEB J 2003;17:341– 348. [PubMed: 12631574] Husi H, Ward MA, et al. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 2000;3:661–669. [PubMed: 10862698] Ideker T, Galitski T, et al. A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet 2001;2:343–372. [PubMed: 11701654] Kennedy MB. The postsynaptic density. CurrOpinNeurobiol 1993;3:732–737. [PubMed: 8260822] Khidekel N, Ficarro SB, et al. Exploring the O-GlcNAc proteome: direct identification of O-GlcNAcmodified proteins from the brain. Proc NatlAcadSci USA 2004;101:13132–13137. [PubMed: 15340146] Lisman J, Schulman H, et al. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 2002;3:175–190. [PubMed: 11994750] Morciano M, Burre J, et al. Immunoisolation of two synaptic vesicle pools from synaptosomes: a proteomics analysis. J Neurochem 2005;95:1732–1745. [PubMed: 16269012]

  20. Tripp G, Wickens JR. Neurobiology of ADHD. Neuropharmacology. 2009;57(7-8):579-89. Epub 2009/07/25. 2. Kurtis MM, Rajah T, Delgado LF, Dafsari HS. The effect of deep brain stimulation on the non-motor symptoms of Parkinson's disease: a critical review of the current evidence. NPJ Parkinson's disease. 2017;3:16024. Epub 2017/07/21. 3. Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz MC, Lehericy S, Bergman H, et al. Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease. Nature reviews Neuroscience. 2010;11(11):760-72. Epub 2010/10/15. 4. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003;39(6):889-909. Epub 2003/09/16. 5. Foster HD, Hoffer A. The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Medical hypotheses. 2004;62(2):177-81. Epub 2004/02/14. 6. Chotibut T, Meadows S, Kasanga EA, McInnis T, Cantu MA, Bishop C, et al. Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. Movement disorders : official journal of the Movement Disorder Society. 2017. Epub 2017/06/21. 7. Foerde K, Braun EK, Higgins ET, Shohamy D. Motivational modes and learning in Parkinson's disease. Social cognitive and affective neuroscience. 2015;10(8):1066-73. Epub 2015/01/02. 8. Zoidl G, Dermietzel R. On the search for the electrical synapse: a glimpse at the future. Cell and tissue research. 2002;310(2):137-42. Epub 2002/10/25. 9. Steward O, Schuman EM. Compartmentalized synthesis and degradation of proteins in neurons. Neuron. 2003;40(2):347-59. Epub 2003/10/15. 10. Wang L, Guo L, Lu L, Sun H, Shao M, Beck SJ, et al. Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease. PloS one. 2016;11(3):e0150441. Epub 2016/03/05. 11. Schrimpf SP, Meskenaite V, Brunner E, Rutishauser D, Walther P, Eng J, et al. Proteomic analysis of synaptosomes using isotope-coded affinity tags and mass spectrometry. Proteomics. 2005;5(10):2531-41. Epub 2005/06/29. 12. Bai F, Witzmann FA. Synaptosome proteomics. Sub-cellular biochemistry. 2007;43:77-98. Epub 2007/10/24. 13. Witzmann FA, Arnold RJ, Bai F, Hrncirova P, Kimpel MW, Mechref YS, et al. A proteomic survey of rat cerebral cortical synaptosomes. Proteomics. 2005;5(8):2177-201. Epub 2005/04/27. 14. Walikonis RS, Jensen ON, Mann M, Provance DW, Jr., Mercer JA, Kennedy MB. Identification of proteins in the postsynaptic density fraction by mass spectrometry. The Journal

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