Kuru: genes, cannibals and neuropathology

Abstract

Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.

FIGURE 1

General views of kuru. (A) A group of Fore men, dcg-57-ng-118. (B) A boy with kuru supported by a father. (C) A woman with kuru, dcg-ng-57-346A. (D) A group of boys with kuru. (E) A boy with kuru being supported by an adolescent, dcg-57-png-1148. (F) An advanced stage of kuru. All slides were taken by the late D. Carleton Gajdusek and given to the first author.

FIGURE 2

Macroscopic view of the kuru brain (“K”) (64). (A) Coronal section. (B) Luxol fast blue stain. (C) Kanzler stain to detect hyperplastic astrocytes. (D) Immunohistochemistry for the transmissible spongiform encephalopathy–specific prion protein PrP^TSE.

FIGURE 3

Neuropathology of kuru. (A) Typical spongiform change. Hematoxylin and eosin stain. (B) Immunohistochemistry for glial fibrillary acidic protein demonstrates astrocyte proliferation. (C) Microglial cells are detected by anti-HLA-DR immunohistochemistry. (D) Numerous enlarged neurites detected using anti-neurofilament protein antibody. (E) Perineuronal accumulation (arrows) of transmissible spongiform encephalopathy–specific prion protein PrP^TSE. (F) Synaptic accumulation of PrP^TSE; an amyloid plaque (arrow) is also visible. (A, E) are from the cerebral cortex; (B–D, F) are from the cerebellum. All are from case “K” (64).

FIGURE 4

Kuru plaques. (A) Hematoxylin and eosin stain (arrow). (B) Transmissible spongiform encephalopathy–specific prion protein (PrP^TSE) immunohistochemistry. (C) Confocal laser microscopy; anti-PrP^TSE antibodies are labeled green; anti–glial fibrillary acidic protein is labeled red. (D) p62 accumulation within Purkinje cells and neurites. (E, F) Transmission electron microscopy. A dystrophic neurite (arrow) is present in (F). All figures are from case “K” (64).