Transmission of proteotoxicity across cellular compartments.

An important subgroup of human neurodegenerative diseases is associated with abnormal expansions of glutamine repeats found in several otherwise unrelated proteins (Zoghbi and Orr 2000). Interest in these polyglutamine diseases is fueled both by their clinical significance and by the belief that lessons gleaned from these relatively rare conditions will apply to other more prevalent human neurodegenerative disorders and perhaps more generally to other diseases of aging. The basis for this belief is the observation that polyglutamine diseases and common neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, share as a common feature the accumulation of abnormal protein aggregates in and around affected neurons (Kaytor and Warren 1999). In the polyglutamine diseases there is a good correlation between the length of the glutamine repeat, the tendency of the affected protein to assume abnormal aggregation-prone states of folding, and the occurrence of neurodegeneration (Gusella and MacDonald 2000; Orr 2001). Furthermore, there is reason to believe that despite the dissimilarities in structure and function of the proteins that “host” the glutamine repeat, once the polyglutamine expansion has reached a critical length, it imposes a common abnormal folding state on the affected protein (Perutz 1996). Together with the dominant inheritance pattern of the associated diseases, these observations suggest that the abnormal polyglutamine repeat converts host proteins into toxic entities, or proteotoxins (Hightower 1991). Attempts to understand the pathophysiology of polyglutamine diseases have therefore focused on the physical state of the abnormal protein, the cellular compartment in which it is found, and the impact of the abnormal protein on cell physiology. A paper in this issue of Genes & Development reports on a pathogenic polyglutamine protein that accumulates as a nuclear aggregate yet triggers the unfolded protein response—a cellular response to unfolded and misfolded proteins in the endoplasmic reticulum (Nishitoh et al. 2002). We will discuss some of the implications of this finding whereby the impact of a polyglutamine-containing proteotoxin can be transmitted from one cellular compartment to another.