By Professor Corinne Lasmezas
Creutzfeldt-Jakob disease (CJD) is a human prion disease, extremely rare yet always fatal. Most cases are sporadic, usually occurring in people over 65 years of age and with an overall incidence around the world of one case per million people.
CJD is a transmissible spongiform encephalopathy; spongiform reflects the condition of the affected brain, which can be, in certain cases, so riddled with vacuoles – storage bubbles – that it resembles a sponge.
CJD may also be genetic, linked to mutations in the gene that produces the prion protein (PrP). Familial cases of other prion diseases are known as Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI).
About 450 cases of iatrogenic CJD (i.e. linked to medical procedures) have been reported. These cases resulted mainly from dura mater grafting – dura mater is the hard membrane that covers and protects the brain and spinal cord – or from transmission of CJD after administration of pituitary-derived growth hormone.
Variant CJD (vCJD), which is slightly different than the classic form of the disease, first appeared in the United Kingdom in 1996 and is linked to the consumption of bovine products contaminated with the bovine spongiform encephalopathy (BSE) prion or mad cow disease.
The total number of vCJD cases worldwide reached 224 in 2013, of which 176 were reported in the UK. Fortunately, due to effective disease control measures, BSE in cattle has almost disappeared.
Kuru is a historical disease that occurred in Papua New Guinea and was transmitted between individuals during cannibalistic funeral feasts. The disease vanished as these rituals were prohibited by the Australian authorities in the early 1950’s.
However, occasional patients still developed the disease up to 50 years after the events occurred, primarily because of the long incubation period of the disease.
Etiology and neuropathology
Prion diseases belong to the family of protein misfolding neurodegenerative diseases that also include Alzheimer’s, Parkinson’s and Huntington’s disease; and amyotrophic lateral sclerosis (Lou Gehrig’s disease). All these diseases are characterized by the misfolding of one or several host proteins, which leads to neurotoxicity.
Prion diseases in humans occur randomly most of the time, but may be acquired through instances of inadvertent transmission during a medical procedure or from zoonotic transmission, defined as a human disease acquired from an animal – precisely how humans became infected during the mad cow disease outbreak in the UK in the mid-1990s.
Prions are thought to be constituted of highly aggregated prion protein (PrP), which is naturally expressed in the body but at higher levels in the brain.
Although many functions have been described for PrP, their significance has yet to be fully established. PrP is thought to modulate synaptic transmission, to participate in homeostasis of metal ions or in myelination.
Prions are classified by distinct strains, characterized by their incubation time and the disease they cause. Prions have the ability to replicate by templating the misfolding of more host prion protein (“seeding”).
Misfolded prion protein is toxic to neurons and causes damage to the brain. Moreover, misfolded prion protein aggregates, sometimes forming large amyloid plaques.
Once thought to be unique, it is now recognized, however, that cell-to-cell transmission of pathologically misfolded proteins and templated misfolding are not restricted to prion diseases, but is a mechanism of the spread of protein pathology from one brain area to another in a variety of other protein misfolding diseases as well.
The hypothesis that prions are proteinaceous infectious particles was formulated in the early 1980’s by Stanley B. Prusiner of the University of California, San Francisco who won the Nobel Prize for Physiology or Medicine 1997 for his prion work.
Several different forms of CJD have been identified. The most common form presents a number of symptoms including progressive dementia, abnormal eye movements or visual impairment, confusion, and lack of movement coordination.
Patients who suffer from the variant form of the disease may show signs of depression and pain in the lower limbs during the very early stages of the disease, with ataxia – lack of movement coordination – as the dominant symptom at a later stage. The course of the disease typically ranges 6 months to 2 years.
The diagnosis of CJD is essentially clinical and confirmed by biochemical tests of the cerebrospinal fluid, electroencephalogram or magnetic resonance imaging findings.
New tests directly measuring aggregated PrP in the cerebrospinal fluid are gradually being implemented. Blood tests are also under development.
Several treatments have shown to delay the appearance of symptoms in experimental animal models of prion diseases such as polyene antibiotics, which primarily target fungal infections; sulfated polyanions, which have been used experimentally in HIV infections; and tetracyclins and more.
None of them, however, has so far been translated into efficacious treatments in the clinic.
Several therapeutic approaches, including drug discovery by high-throughput screening, are being investigated by various research groups around the world.
Some approaches aim at preventing the conversion of PrP into its pathogenic conformation, and a recently published new approach consists of reducing host levels of PrP altogether in order to halt the pathogenic process. These research efforts show promise towards the goal to make CJD a treatable disease.
About Corinne Lasmezas
Corinne Lasmezas, a professor on the Florida campus of The Scripps Research Institute (TSRI), studies the mechanisms of prion propagation and neurotoxicity, and investigates novel approaches to the therapeutics and prophylaxy of prion diseases.
Just prior to joining TSRI in 2005, she was director of the Laboratory for Prion Pathogenesis in the Department of Medical Research, Atomic Energy Commission, Fontenay-aux-Roses, France.
She received her Ph.D. in neurosciences from the Pierre and Marie Curie University in Paris.
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