Stochastic kinetics of intracellular huntingtin aggregate formation.
Neurodegeneration in Huntington disease is described by neuronal loss in which the probability of cell death remains constant with time. However, the quantitative connection between the kinetics of cell death and the molecular mechanism initiating neurodegeneration remains unclear. One hypothesis is that nucleation of protein aggregates containing exon I fragments of the mutant huntingtin protein (mhttex1), which contains an expanded polyglutamine region in patients with the disease, is the explanation for the infrequent but steady occurrence of neuronal death, resulting in adult onset of the disease. Recent in vitro evidence suggests that sufficiently long polyglutamine peptides undergo a unimolecular conformational change to form a nucleus that seeds aggregation. Here we use this nucleation mechanism as the basis to derive a stochastic mathematical model describing the probability of aggregate formation in cells as a function of time and mhttex1 protein concentration, and validate the model experimentally. These findings suggest that therapeutic strategies for Huntington disease predicated on reducing the rate of mhttex1 aggregation need only make modest reductions in huntingtin expression level to substantially increase the delay time until aggregate formation.
Colby
David W
DW
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cassady
John P
JP
Lin
Grace C
GC
Ingram
Vernon M
VM
Wittrup
K Dane
KD
D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D005091:Exons; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D007700:Kinetics; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013269:Stochastic Processes; D013997:Time Factors; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine