Coaggregation of polyglutamine (polyQ) proteins is mediated by polyQ-tract interactions and impairs cellular proteostasis

Abstract

Nine polyglutamine (polyQ) proteins have already been identified that are considered to be associated with the pathologies of neurodegenerative disorders called polyQ diseases, but whether these polyQ proteins mutually interact and synergize in proteinopathies remains to be elucidated. In this study, 4 polyQ-containing proteins, androgen receptor (AR), ataxin-7 (Atx7), huntingtin (Htt) and ataxin-3 (Atx3), are used as model molecules to investigate their heterologous coaggregation and consequent impact on cellular proteostasis. Our data indicate that the N-terminal fragment of polyQ-expanded (PQE) Atx7 or Htt can coaggregate with and sequester AR and Atx3 into insoluble aggregates or inclusions through their respective polyQ tracts. In vitro coprecipitation and NMR titration experiments suggest that this specific coaggregation depends on polyQ lengths and is probably mediated by polyQ-tract interactions. Luciferase reporter assay shows that these coaggregation and sequestration effects can deplete the cellular availability of AR and consequently impair its transactivation function. This study provides valid evidence supporting the viewpoint that coaggregation of polyQ proteins is mediated by polyQ-tract interactions and benefits our understanding of the molecular mechanism underlying the accumulation of different polyQ proteins in inclusions and their copathological causes of polyQ diseases.

PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6

“…However, the 23Q forms of Atx2 and its fragment had only little effect on the FL/RL ratio. We also set Htt-N552 as a control ( 66 , 67 ), in which overexpression of Htt 100Q -N552 did not affect the MARF1 activity at all ( Fig. 7 B ).…”

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

“…This is sometimes referred to as 'cross-talk' or 'cross-feeding', heterotypic interaction [310, 311], and -perhaps most commonly -'crossseeding' [169, . Note that even simple polyQ features (occuring as C-terminal 'tails' in various diseases) can do this [324,[350][351][352][353][354], possibly also by incorporating transition metals [355]. Equually importantly, not all amyloids ('donors') can cross-seed other ones [139] ('acceptors') and hence be entrapped in the fibrils of the acceptors; there is significant selectivity, whose sequence/structural basis remains unknown.…”