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Alpha-synuclein in Parkinson's disease L 529 Presentation Harini Gopalakrishnan, Keval Mehta and Sourav Roy Outline Wednesday, May 24, 2017 The disease The protein The pathway About CATPA CATPA demo L529 Presentation 2 Parkinson’s Disease The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 Parkinson's disease is a progressive, degenerative neurological disorder Symptoms are tremor, rigidity, difficulty coordinating movement and difficulty with balance The dopamine-producing neurons in the part of the brain responsible for coordinating muscle movement die or become so damaged that they are no longer functional. Recent findings suggest that misfolding of the protein alpha-synuclein (aS), has been implicated in the molecular chain of events leading to Parkinson's disease (Ulmer et al., 2005) There is no way to prevent its onset and once diagnosed, it has no cure. Treatment is limited to ameliorating symptom L529 Presentation 3 Genes Involved The disease The protein The pathway SNCA: Synuclein, alpha (non A4 component of amyloid precursor); PARK2: Parkinson disease (autosomal recessive, juvenile) 2, parkin; DJ-1 PINK1 DRDN LRRK2 most recent. About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 4 Parkinson’s disease and α-synuclein The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 Second most common neurodegenerative disease; An “environmental” disease (pesticides and metals); Due to death of dopaminergic neurons in the substantia nigra; Pathological hallmark is intracellular proteinaceous inclusions called Lewy bodies and Lewy neurites; Major protein component in LBs and LNs is αsynuclein; Substantial evidence implicates the aggregation of αsynuclein as a key factor in the etiology of Parkinson’s disease L529 Presentation 5 Parkinson’s diseases The disease Parkinson’s disease is likely to be multifactorial Nine Scientific Pathways to Understanding Parkinson ’s Genetic factors Protein misfolding and aggregation Oxidative stress Excitotoxicity Mitochondrial impairment Microglial activation Loss of trophic factors Over-activity of basal ganglia output and apoptosis The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 6 The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 7 α-synuclein The disease The protein The disease is thought to be due to a toxic overaccumulation of the protein α-synuclein; which results in cell degeneration and death. One form of inherited Parkinson's is associated with mutations in the alpha-synuclein gene that cause overexpression of the alpha-synuclein protein resulting in the formation of Lewy bodies. A more common, recessive form of inherited Parkinson's disease is linked to a mutation in the parkin gene. The loss of enzyme activity resulting from this mutation leads to an accumulation of protein substrates, including alpha-synuclein, in the cell. The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 8 The Pathway The disease The protein The pathway • What is known is that the O-glycosylated SNCA is ubiquitinated and transformed into Ub SNCA, PARK2 is believed to activate this process. • The Ub SNCA ultimately forms the degraded Alphasynuclein through the Proteosome pathway. • If Alpha-synuclein degradation is blocked or defective, it aggregates to form the Lewy Body, which ultimately results in the dopaminergic cell death About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 9 The basal ganglia controls movement and balance The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 10 Disorder in α-synuclein The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 11 CATPA The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 12 6 –Residue Repeat Region The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 13 Alignment Overview-1 The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 14 Alignment Overview-2 The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 15 CATPA DEMO The disease The protein The pathway About CATPA CATPA demo Wednesday, May 24, 2017 L529 Presentation 16 Thanks very much! References: 1.Ulmer et al., Structure and dynamics of micelle-bound human alphasynuclein; J.Biol.Chem. v280 pp. 9595-603, 2005. 2. Parkinson’s information website - http://www.parkinsonsinfo.com 3.Biocarta databases – http://www.biocarta.com 4.Kyoto Encyclopedia of Genes and Genomes databases – http://www.genome.ad.jp: KEGG Kyoto Encyclopedia of Genes and Genomes 5.National Parkinson Foundation – http://www.parkinson.org/site/pp.asp?c=9dJFJLPwB&b=71117 6. Information hyperlinked over proteinshttp://www.ihop- net.org/UniPub/iHOP/gs/92293.html 7. Medical News Today – http://www.medicalnewstoday.com/medicalnews.php?newsid=17028 8. American Parkinson Disease Inc - http://www.apdaparkinson.org 9. Uversky et al. Trimethylamine-N-oxide-induced folding of alpha-synuclein FEBS Lett. 2001; 509(1):31-35. Wednesday, May 24, 2017 L529 Presentation 17