Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum.

The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by the accumulation of mutant neuroserpin within neurons (Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, D., Muenke, M., Lawrence, D. A., Yerby, M. S., Shaw, C.-M., Gooptu, B., Elliott, P. R., Finch, J. T., Carrell, R. W., and Lomas, D. A. (1999) Nature 401, 376-379), but little is known about the trafficking of wild type and mutant neuroserpins. We have established a cell model to study the processing of wild type neuroserpin and the Syracuse (S49P) and Portland (S52R) mutants that cause FENIB. Here we show that Syracuse and Portland neuroserpin are retained soon after their synthesis in the endoplasmic reticulum and that the limiting step in their processing is the transport to the Golgi complex. This is in contrast to the wild type protein, which is secreted into the culture medium. Mutant neuroserpin is retained within the endoplasmic reticulum as polymers, similar to those isolated from the intraneuronal inclusions in the brains of individuals with FENIB. Remarkably, the Portland mutant showed faster accumulation and slower secretion compared with the Syracuse mutant, in keeping with the more severe clinical phenotype found in patients with the Portland variant of neuroserpin. Both mutant and wild type neuroserpin were partially degraded by proteasomes. Taken together, our results provide further understanding of how cells handle defective but ordered mutant proteins and provide strong support for a common mechanism of disease caused by mutants of the serine protease inhibitor superfamily.