An autopsy report of three kindred in a Gerstmann–Sträussler–Scheinker disease P105L family with a special reference to prion protein, tau, and beta-amyloid

Abstract

Introduction: Gerstmann–Sträussler–Scheinker disease P105L (GSS105) is a rare variant of GSS caused by a point mutation of the prion protein (PrP) gene at codon 105 (proline to leucine substitution). It is clinically characterized by spastic paraparesis and dementia and histopathologically defined by PrP-plaques in the brain. This report describes a clinicopathological analysis of three autopsied kindred from a Japanese GSS105 family, plus a topological analysis of PrP, hyperphosphorylated tau (p-tau), and beta-amyloid (Aβ). Methods: Using paraffin-embedded sections, we applied histology and single- and multiple-labeling immunohistochemistry for PrP, p-tau, and Aβ to the three cases. Comparative semi-quantitative analyses of tissue injuries and PrP-plaques were also employed. Results: Case 1 (45 years old (yo)) and Case 2 (56 yo) are sisters, and Case 3 (49 yo) is the son of Case 2. Case 1 and Case 2 presented with spastic paraparesis followed by dementia, whereas Case 3 presented, not with spastic paraparesis, but with psychiatric symptoms. In Case 1 and Case 2, the brain showed tissue injuries with many PrP-plaques in the cerebral cortices, and the pyramidal tract showed myelin loss/pallor. In Case 3, the brain was least degenerated with a number of PrP-plaques; however, the pyramidal tract remained intact. In addition, p-tau was deposited in all cases, where p-tau was present in or around PrP-plaques. By double-labeling immunohistochemistry, the colocalization of p-tau with PrP-plaques was confirmed. Moreover in Case 2, Aβ was deposited in the cerebral cortices. Interestingly, not only p-tau but also Aβ was colocalized with PrP-plaques. In all cases, both three repeat tau and four repeat tau were associated with PrP-plaques. Conclusions: The clinicopathological diversity of GSS105, which is possible even in the same family, was ascertained. Not only p-tau but also Aβ could be induced by PrP (“secondary degeneration”), facilitating the kaleidoscopic symptoms of GSS.