Differential pathology of P102L-associated Gerstmann–Stäussler–Scheinker disease: exclusive presence of 8-kDa protease-resistant prion protein vs. co-existence of 8-kDa and type-1 protease-resistant prion protein, with a focus on codon 129 polymorphi

Gerstmann - Sträussler - Scheinker disease (GSS) is a hereditary prion disease characterized by clinicopathological heterogeneity. In Japan, the most common mutation is P102L, typically associated with prion protein (PrP) plaques, spongiform changes, and synaptic PrP deposits. Two major protease-resistant PrP (PrP^res) types occur: type-1 PrP^res (21 kDa) and 8-kDa PrP^res. The <i>PRNP</i> codon 129 polymorphism (methionine or valine) influences disease phenotype, but factors underlying exclusive 8-kDa PrP^res expression remain unclear. We analysed two sibling P102L GSS cases exclusively exhibiting 8-kDa PrP^res (Case 1: 129 MM, haplotype: P102L-129 M, treated with pentosan polysulfate; Case 2: 129 MV, haplotype: P102L-129 M, treated with quinacrine hydrochloride and quinine hydrochloride) and four P102L-129 MM GSS cases exhibiting type-1 and 8-kDa PrP^res (Cases 3-6) to elucidate the clinicopathological effect of 8-kDa PrP^res and <i>PRNP</i> codon 129 polymorphisms. Case 1 predominantly exhibited amyloidogenic PrP plaques; Case 2 exhibited non-amyloidogenic cotton-wool PrP plaques, with minimal synaptic PrP deposits. Despite prolonged survival ( > 20 years), spongiform degeneration and neuronal loss were mild. Cases 3-6 showed numerous amyloidogenic PrP plaques, moderate-to-severe synaptic PrP deposits, and significant tissue damage. Homoeostatic microglial markers were preserved in Cases 1 and 2 but absent in Cases 3-6. Cotton-wool PrP plaques lacked amyloid cores and were associated with 8-kDa PrP^res and codon 129 V from the normal allele. Tissue damage was mild in P102L GSS cases exhibiting 8-kDa PrP^res, suggesting lower pathogenicity. Cotton-wool PrP plaque formation likely involves 8-kDa PrP^res and codon 129 V. Further large-scale studies are warranted to elucidate these mechanisms.