A central mystery in age-related diseases of protein folding is why they’re age-related. Specifically, for many if not most well-studied neurodegenerative conditions with protein folding abnormalities or protein aggregation at their root — Alzheimer’s, Huntington’s, Parkinson’s, and sporadic (as opposed to infectious) prion disease — age is a major risk factor. Why?
One possibility is that accumulation of toxic misfolded or aggregated species simply requires time, and the major difference between old and young organisms is that the former have been around longer. Studies in model organisms in which the rate of aging can be genetically controlled, however, has started to point toward biological aging (i.e., cellular and molecular changes that occur more slowly in slower-aging organisms), rather than simple chronological aging (i.e., the passage of time), as the principal risk factor. (For further discussion about the results in C. elegans, see our earlier article, Pulling apart proteotoxicity.)
Assuming for the moment that biological aging is the more significant factor, what is the nature of the relevant cellular and molecular changes? One candidate is an alteration in post-translational protein modification. In support of this idea, Goh et al. demonstrate that PrPC, the protein involved in prion diseases, exhibits age-related changes in N-linked glycosylation:
The normal cellular prion protein (PrPC) is a glycoprotein with two highly conserved potential N-linked glycosylation sites. All prion diseases, whether inherited, infectious or sporadic, are believed to share the same pathogenic mechanism that is based on the conversion of the normal cellular prion protein (PrPC) to the pathogenic scrapie prion protein (PrPSc). However, the clinical and histopathological presentations of prion diseases are heterogeneous, depending not only on the strains of PrPSc but also on the mechanism of diseases, such as age-related sporadic vs. infectious prion diseases. Accumulated evidence suggests that N-linked glycans on PrPC are important in disease phenotype. A better understanding of the nature of the N-linked glycans on PrPC during the normal aging process may provide new insights into the roles that N-linked glycans play in the pathogenesis of prion diseases. By using a panel of 19 lectins in an antibody–lectin enzyme-linked immunosorbent assay (ELISA), we found that the lectin binding profiles of PrPC alter significantly during aging. There is an increasing prevalence of complex oligosaccharides on the aging PrPC, which are features of PrPSc. Taken together, this study suggests a link between the glycosylation patterns on PrPC during aging and PrPSc.
The findings are of obvious interest to the study of sporadic prion disease, but there are also broader ramifications: If PrPC is being differentially glycosylated with age, might other proteins passing through the secretory pathway also be affected? (It seems likely that the modification would not be limited to a single protein; then again, PrPC is known to be unusual, so the jury is still out.)
The implications extend beyond neurodegenerative disease to the broader issue of how basic cellular processes are altered with age. Study of age-related alterations in protein glycosylation may tell us a great deal about the progress of normal, non-pathological cellular aging.