Letters to the Editor

Transmission of fatal familial insomnia to laboratory animals

Over the past decade, small extracellular vesicles called exosomes have been observed to harbour protein and genetic cargo that can assist in health and also cause disease. Many groups are extensively investigating the mechanisms involved that regulate the trafficking and packaging of exosomal contents and how these processes may be deregulated in disease. Prion diseases are transmissible neurodegenerative disorders and are characterized by the presence of detectable misfolded prion proteins. The disease associated form of the prion protein can be found in exosomes and its transmissible properties have provided a reliable experimental read out that can be used to understand how exosomes and their cargo are involved in cell-cell communication and in the spread of prion diseases. This review reports on the current understanding of how exosomes are involved in the intercellular spread of infectious prions. Furthermore, we discuss how these principles are leading future investigations in developing new exosome based diagnostic tools and therapeutic drugs that could be applied to other neurodegenerative diseases.

Fatal familial insomnia (FFI) and sporadic fatal insomnia (sFI), or thalamic form of sporadic Creutzfeldt–Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene (PRNP) at chromosome 20. sFI is a phenocopy of FFI and likely its sporadic form. Both diseases are primarily characterized by progressive sleep impairment, disturbances of autonomic nervous system, and motor signs associated with severe loss of nerve cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of 19 kDa identified as resPrP^TSE type 2. To date at least 70 kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is thought to cause FFI by destabilizing the mutated prion protein and facilitating its conversion to PrP^TSE. The thalamus is the brain region first affected. A similar mechanism triggered spontaneously may underlie sFI.

Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible. Genetic studies with the tools of molecular biology and transgenic mice forced a reevaluation of earlier work and supported the prion hypothesis of a novel pathogen devoid of nucleic acid. In this chapter, I discuss the contributions of classical and molecular genetics to understanding PrP prion diseases and to determining that heritable information is enciphered in protein conformation.

A 75-year-old man presented with a three-year history of progressively worsening insomnia and dementia. His mother and older sister had similar disorders. On initial examination, he was awake, apathetic, and disoriented but had no focal neurological deficits. Electroencephalography showed diffuse background slowing with neither periodic discharge nor sleeping activity. A single-photon emission CT scan showed significantly reduced cerebral perfusion in bilateral thalami, basal ganglia, and limbic cortices. In the late stage of his illness, he developed sphincter dysfunction. Laboratory studies showed increased T-lymphocytes and B-lymphocytes and reduced cortisol level. Cerebrospinal fluid 14-3-3 protein was absent. Genetic evaluations failed to show the aspartate to asparagine point mutation at codon 178 but disclosed an asparagine to serine substitution at codon 171 in one allele and a deletion of 24 base pairs in the other allele in the human prion protein gene. These findings led to a diagnosis of sporadic fatal insomnia, which is a recently described prion disease.