Neurotoxic protein oligomerisation associated with polyglutamine diseases.
Polyglutamine (polyQ) diseases are associated with a CAG/polyQ expansion mutation in unrelated proteins. Upon elongation of the glutamine tract, disease proteins aggregate within cells, mainly in the central nervous system (CNS) and this aggregation process is associated with neurotoxicity. However, it remains unclear to what extent and how this aggregation causes neuronal dysfunction in the CNS. Aiming at preventing neuronal dysfunction, it will be crucial to determine the links between aggregation and cellular dysfunction, understand the folding pathway of polyQ proteins and discover the relative neurotoxicity of polyQ protein species formed along the aggregation pathway. Here, we review what is known about conformations of polyQ peptides and proteins in their monomeric state from experimental and modelling data, how conformational changes of polyQ proteins relate to their oligomerisation and morphology of aggregates and which cellular function are impaired by oligomers, in vitro and in vivo. We also summarise the key modulatory cellular mechanisms and co-factors, which could affect the folding pathway and kinetics of polyQ aggregation. Although many studies have investigated the relationship between polyQ aggregation and toxicity, these have mainly focussed on investigating changes in the formation of the classical hallmark of polyQ diseases, i.e. microscopically visible inclusion bodies. However, recent studies in which oligomeric species have been considered start to shed light on the identity of neurotoxic oligomeric species. Initial evidence suggests that conformational changes induced by polyQ expansions and their surrounding sequence lead to the formation of particular oligomeric intermediates that may differentially affect neurotoxicity.
Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK.
Sarah L
SL
Hands
Andreas
A
Wyttenbach
D000818:Animals; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017510:Protein Folding
D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine