Cellular homeostasis is an exceedingly complex process. Conceptually, one may
consider two regimes within which the phenomenon operates, extra- and intracellular.
The extracellular regime requires dynamic responses of the cell to
external stimuli. The intracellular regime involves metabolic processes that neurologists
might refer to as “activities of daily living,” those processes that the
cell must execute continuously to function normally. One of these activities is
the synthesis and folding of proteins. This activity is highly efficient overall,
but imperfect. A significant percentage of nascent proteins fold improperly,
even with the help of folding chaperones, and thus must be “recycled” through
proteolysis in the proteasome system. What happens if the capacity of the
protein folding and degradation machinery is exceeded?
In a paper published on 9 February in Sciencexpress, Morimoto and colleagues
at Northwestern University address the general question raised above from the
perspective of diseases of protein aggregation that cause neurodegenerative disorders.
The authors have elegantly demonstrated the importance of the presence of intracellular misfolded proteins in mediating cellular dysfunction in neurodegenerative disease. Coexpressing the temperature-sensitive (ts) mutants with polyQ in C. elegans
at permissive conditions resulted in phenotypes similar to those exhibited by ts mutants under restrictive conditions. This conversion of relatively harmless ts mutants into those which exhibit mutant phenotypes under permissive conditions is a fascinating and enlightening observation. The experiments with various other strains of ts mutants make the case that the expression of aggregation-prone polyQ protein meddles with the structure and function of unrelated proteins. Specifically, the authors suggest that the levels of polyQ influence the folding of ts protein and that perhaps the opposite is also true, as though a positive feedback mechanism exists to augment the imbalance in cellular folding.
In interpreting the results, the authors propose that marginally stable proteins do not in and of themselves cause disease;...