Protein misprocessing and aggregation have been observed in many neurodegenerative diseases, including Alzheimer’s, spongiform encephalopathies, Huntington’s, Parkinson’s and FTDP-17, but it has been difficult to untangle the causal relationship between protein deposition to clinical disease. This link has now been more persuasively established in a newly reported familial dementia caused by mutations in the gene for neuroserpin, according to a report in tomorrow’s issue of Nature. Neuroserpin belongs to a family of serine proteinase inhibitors (serpins).

The disease-causing mutations were identified in two Caucasian families, and cause an autosomal dominant disorder characterized by deficits in attention, visuospatial skills and memory, although the latter not to the degree seen in Alzheimer’s disease. Symptoms appear around the fifth decade in the larger family, and by the third or fourth decade in the smaller family, with a course of 10-15 years. Brain autopsies revealed the presence of neuronal inclusions throughout the deeper layers of the cerebral cortex and in many subcortical nuclei, particularly in the substantia nigra. The inclusions turned out to consist primarily of neuroserpin.

In one of the families, the neuroserpin mutation was homologous to a mutation in α1 antitrypsin that results in a cirrhosis of the liver with inclusion bodies. The mutation destabilizes the proteins in such a way as to promote aggregation. What’s more, only those α1 antitrypsin mutations that result in cirrhosis are those that cause aggregation of the protein, strongly suggesting that it is the aggregation, per se, that causes the disease. “So we suspect that this is also true in the brain, that the neuroserpin mutation results in a "gain of function" caused by aggregation, rather than a loss of the normal function of neuroserpin,” says Antony Shrimpton, a co-author on the paper. The finding lends support, by analogy, to the argument that protein aggregation has a causal role in other neurodegenerative diseases.—Hakon Heimer


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  1. . Familial dementia caused by polymerization of mutant neuroserpin. Nature. 1999 Sep 23;401(6751):376-9. PubMed.