January 13, 2014

Proteins can form oligomers or amorphous aggregates

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Unformatted text preview: aberrant protein structure and aggregation in amyloid related diseases: The process is initiated by denaturation, unfolding, or misfolding (indicated by the transition from blue triangle to red circle). Proteins can form oligomers or amorphous aggregates or small, structured polymers known as protofibrils. Protofibrils mature into amyloid fibrils and then into aggregates of amyloid fibrils. Current data indicate that all aberrant protein structures (i.e., all structures shown other than the native monomer) are toxic O. Hardiman and C.P. Doherty (eds.), Neurodegenerative Disorders, DOI: 10.1007/978-1-84996-011-3_1, © Springer-Verlag London Limited 2011 Cellular response to protein misfolding • Cells can refold the protein using molecular chaperones • Can be targeted by lysosomes or proteosomes for degradation • Can form aggresomes where it can be degraded by macroautophagy Cell can get rid of misfolded proteins Abnormal conformation/ either use molecular chaperone which will help unfold protein and then fold it back properly again can be targeted by lysosomes or proteosomes by degradation ( misfolded protein can be degenrated) Agresome can be broken down by macroautophagy. When we have lots of misfolded proteins we can get it by macroautography. Refold or get rid of them However, the cell cannot always remove aggregates • In Alzheimer’s disease • Intracellular depositions – -amyloid plaque • Extracellular depositions – neurofibrillary tangles and hyperphosphorylated tau protein Bossy-Wetzel E, et al., Nat Med. 2004 Jul;10 Suppl:S2-9. Review. Our cells are unable to get rid or refold / AD you have intracellular of BA and extracelllar build up of tau proteins However, the cell cannot always remove aggregates • In Parkinson’s disease • Lewy bodies – comprised of -synuclein and ubiquitin Bossy-Wetzel E, et al., Nat Med. 2004 Jul;10 Suppl:S2-9. Review. in PD, we have build up for lewy bodies. However, the cell cannot always remove aggregates • In Huntington’s disease • Huntingtin protein forms inclusion bodies contacting ubiquitin Ross CA, Poirier MA. Nat Med. 2004 Jul;10 Suppl:S10-7. Review. in...
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