br Concluding remarks and future perspectives While the rati

Concluding remarks and future perspectives While the rational engineering of protein-based switches has yet to be fully developed, emerging empirical rules facilitate the construction of tailor-engineered amyloid definition with custom input and output parameters. Both in the context of molecular diagnostics and cellular signaling, the future trend will be to assemble separately engineered protein-based sensors, transducer and actuators into autonomous signaling motifs that operate both independently and in parallel to their environment (Box 3).
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Introduction The eponymous name Gerstmann–Sträussler–Scheinker (GSS) disease, introduced in the literature by Schlote et al. (1980), originates from the names of the authors of the scientific report, describing the neuropathologic features of a patient from the Austrian family “H” (Gerstmann et al., 1936). A dominantly inherited neurologic disorder had affected multiple generations of the “H” kindred and in 1912, 1928, and 1936, the main characteristics of the disease's clinical and pathologic phenotypes had been described in two affected family members (Dimitz, 1913; Gerstmann, 1928; Gerstmann et al., 1936). Cerebellar ataxia, dysdiadochokinesia, as well as action and intention tremor were the initial symptoms. With progression of the disease, the patients became unable to walk, stand, or sit upright; they had a disturbance of speech, swallowing difficulties, lateral and vertical gaze nystagmus, and bilateral Babinski signs. They had behavioral and mood alterations as well as a cognitive decline. At the macroscopic examination of the brain, atrophy of the cerebral hemispheres and the cerebellar vermis were described. The histologic analysis revealed the presence of focal deposits of an amorphous substance in the cerebral cortex, basal ganglia, and cerebellum. These deposits had single or multiple cores and, although morphologically different from the senile plaques found in Alzheimer disease, similarities with the senile plaques were noted (Gerstmann et al., 1936). The neuropathology of four additional family members was reported: one case by von Braunmühl in 1954 and three by Seitelberger in 1962. Seitelberger emphasized both the presence of mild to moderate spongiform changes as well as the morphologic similarity of the focal deposits to the plaques occurring in the prion disease known as kuru (Seitelberger, 1962, Seitelberger, 1981). Masters et al. (1981) studied the clinicopathologic data from hereditary syndromes, similar to that reported in Austrian family “H,” and carried out experimental studies, inoculating brain tissue from affected individuals of some of these kindreds into primates. Two main facts emerged: (1) amyloid deposits are a constant pathologic feature, but spongiform changes are not always present; and (2) a spongiform encephalopathy developed in the recipient animals, following brain tissue inoculation. These results were seminal in establishing a possible pathogenetic link between a dominantly inherited neurodegenerative cerebral amyloidosis and Creutzfeldt–Jakob disease (CJD). In 1985, a GSS-like dominantly inherited disease was described in members of a large Indiana kindred; the condition was clinically characterized by ataxia, parkinsonism, and dementia. Neuropathologic studies revealed numerous multicentric amyloid plaques in the parenchyma of the cerebrum and cerebellum (Azzarelli et al., 1985). However, a unique and previously unrecognized neuropathologic feature was the coexistence of amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical nuclei. The neurofibrillary tangles were made of paired helical filaments that, in pictures obtained by transmission electron microscopy, appeared identical to those seen in Alzheimer disease. In 1987, amyloid plaques, from an individual with a GSS-like disorder, were immunolabeled using antibodies raised against PrP and in 1988, the coexistence between prion protein (PrP)-immunopositive amyloid plaques and tau-immunopositive neurofibrillary tangles was demonstrated in the brain tissue of affected individuals from the Indiana kindred (Kitamoto et al., 1987; Ghetti et al., 1988, Ghetti et al., 1989).