A cellular perspective on conformational disease: the role of genetic background and proteostasis networks

Abstract

The inherently error-prone nature of protein biosynthesis and turnover leads to a constant flux of destabilized proteins. Genetic mutations in conformational disease-associated proteins, as well as exposure to acute and chronic proteotoxic stresses, further increase the load of misfolded protein on the proteostasis network. During aging, this leads to enhanced instability of the proteome, failure to buffer destabilizing genetic mutations or polymorphisms, and cellular decline. The combination of cell-type-specific differences in the buffering capacity of the proteostasis network and destabilizing polymorphisms in the genetic background may account for some of the cell-type specificity observed in disease, even when the predominant disease-associated protein is widely expressed.

Figure 1

a–b. Expression of Q40-YFP (Q40, green) in nematodes carrying a destabilizing mutation in paramyosin (par(ts), red) causes mislocalization (a) and misfolding (b) of paramyosin. a, immunostaining and epifluorescence; b, limited proteolysis. c. Q40-YFP itself displays early onset of aggregation when expressed in a ts background. a–c are adapted from Gidalevitz et. al. Science 2006; 311(5766):1471–4. d. Mislocalized par(ts) (green) in an otherwise WT background is seen as early as day 3 of adulthood, and is similar in appearance to the par(ts) at the restrictive temperature (a). Actin filaments counterstained in red. e. Quantification of the number of cells with disrupted myofilaments in par(ts) or WT worms. d–e are adapted from Ben-Zvi et. al., Proc Natl Acad Sci U S A. 2009;106(35):14914–9.

Figure 2

a–b. Proteostasis networks buffer metastable and misfolded species, ensuring normal cellular function. c–d. Failure of proteostasis networks to buffer misfolding results in onset of dysfunction. Accumulated protein damage, proteotoxic stresses and aging all contribute to the increase in misfolding and thus to the decline in the proteostasis network capacity. Either a single dominant mutation (d), or a cumulative effect of milder destabilizing mutations and polymorphisms (c) may lead to the cell-specific dysfunction of sensitized pathways and protein complexes, by competing for a shared limiting component(s) of the proteostasis network.