Protein Toxicity in Parkinson And Alzheimer’s Disease Chuck Sanders, Dept. of Biochemistry Rm...
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Protein Toxicity in Parkinson And Alzheimers Disease Chuck Sanders, Dept. of Biochemistry Rm 5110C MRBIII, Protein Toxicity in Parkinson And Alzheimers Disease Chuck Sanders, Dept. of Biochemistry Rm 5110C MRBIII, Readings on Role of -Synuclein in Parkinson Disease 100 years of Lewy pathology. Goedert M, Spillantini MG, Del Tredici K, Braak H. Nat Rev Neurol Jan;9(1): -Synuclein: membrane interactions and toxicity in Parkinson's disease. Auluck PK, Caraveo G, Lindquist S. Annu Rev Cell Dev Biol. 2010;26: Pathological roles of -synuclein in neurological disorders. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Lancet Neurol Nov;10(11): -Synuclein oligomers and clinical implications for Parkinson disease. Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. Ann Neurol Aug 28. doi: /ana AD From: May 2010 US National Vital Statistics Report PD Protein Deposition in Neurodegenerative Diseases: A Histological View A. Abbott Nature Outlook 2011 NEJM 349, 583 (2003) note that list is incomplete and growing Key Questions About Protein Aggregation in Alzheimers and Parkinson Diseases What triggers protein aggregation? In inherited form of disease? In sporadic (idopathic) form of disease? What form of the protein is toxic? Disease promoted by toxic gain of function, loss of native function, or both? What organ, tissue, and cells are affected as a function of time? Where in (or out) of cell does protein aggregate, deposit and exert its toxicity? What is the mechanism of toxicity and is it direct or pathway-based? Does protein deposition spread from cell to cell and tissue to tissue? If so, how? Before we explore these issues, we need to review the biophysics and biochemistry of protein folding and misfolding. Thermodynamic Stability of Proteins Standard Free Energies of Folding for Single Domain Proteins Protein G o fold (kcal/mol) lambda repressor-3.0 alpha spectrin SH3 domain-2.9 arc repressor-6.3 cytochrome C (with heme and Fe(II)-15 CD2-8.2 procarboxypeptidase-4.1 U1A spliceosomal protein-9.3 Hpr -4.6 Most folding proteins are only moderately stable: The folded state is usually favored over the unfolded state by only -3 to -10 kcal/mol. Many Proteins are Natively Unfolded (Natively Disordered) The unfolded state is energetically favored, unless some the protein comes in contact with something that stabilizes the folded state (e.g., a cognate ligand or a membrane). Polypeptides