ABSTRACT
To explore pathogenesis in a young Gerstmann-Sträussler-Scheinker Disease (GSS) patient, the corresponding mutation, an eight-residue duplication in the hydrophobic region (HR), was inserted into the wild type mouse PrP gene. Transgenic (Tg) mouse lines expressing this mutation (Tg.HRdup) developed spontaneous neurologic syndromes and brain extracts hastened disease in low-expressor Tg.HRdup mice, suggesting de novo formation of prions. While Tg.HRdup mice exhibited spongiform change, PrP aggregates and the anticipated GSS hallmark of a proteinase K (PK)-resistant 8 kDa fragment deriving from the center of PrP, the LGGLGGYV insertion also imparted alterations in PrP's unstructured N-terminus, resulting in a 16 kDa species following thermolysin exposure. This species comprises a plausible precursor to the 8 kDa PK-resistant fragment and its detection in adolescent Tg.HRdup mice suggests that an early start to accumulation could account for early disease of the index case. A 16 kDa thermolysin-resistant signature was also found in GSS patients with P102L, A117V, H187R and F198S alleles and has coordinates similar to GSS stop codon mutations. Our data suggest a novel shared pathway of GSS pathogenesis that is fundamentally distinct from that producing structural alterations in the C-terminus of PrP, as observed in other prion diseases such as Creutzfeldt-Jakob Disease and scrapie.
Subject(s)
Gerstmann-Straussler-Scheinker Disease/genetics , Mutation , PrPSc Proteins/chemistry , PrPSc Proteins/genetics , Prion Diseases/genetics , Adult , Alleles , Amino Acid Sequence , Animals , Humans , Mice , Mice, Transgenic , Middle Aged , Peptide Fragments/genetics , PrPSc Proteins/metabolism , Protein Domains/genetics , Protein Precursors/chemistry , Protein Precursors/geneticsABSTRACT
Aphemia is an apraxia of speech characterized by complete articulatory failure in the presence of preserved writing, comprehension and oropharyngeal function and can be the presenting manifestation of acute stroke. The responsible lesion is commonly in the left inferior frontal gyrus or the left motor cortex near the face M1 area. Three patients who developed aphemia due to acute ischemic stroke are described here. All had apraxia of speech due to acute infarct in the left motor cortex near face M1 area. Understanding the underlying speech disorder is crucial in planning the appropriate rehabilitation strategy.
