Prion Diseases and Copper Metabolism. Bse, Scrapie and Cjd Research

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Clinical symptoms which may show intrafamilial and intragenerational variation include cerebellar ataxia, gait abnormalities, dementia, dysarthria, ocular dysmetria, infrequent myoclonus, spastic paraparesis, parkinsonian signs, and hyporeflexia or areflexia in the lower extremities [ 28 , 29 ]. However, legs hyperreflexia from an early disease course has recently been seen in a Japanese GSS patient carrying the PL mutation [ 54 ].

In GSS, altered sleep and temperature rhythms may also be noticed [ 55 ]. When linked to V allele, PL, which is the most common cause of GSS, resulted in the predominance of psychiatric signs such as apathy and depression [ 56 ]. YN demonstrated clinical criteria for possible Alzheimer disease and possible frontotemporal dementia, with neurofibrillary degeneration on neuropathological profiles, and various PrP Sc fragments in the range of kDa [ 58 ].

CJD Creutzfeldt-Jakob Disease - Mayo Clinic

In general, neuropathologic features of GSS patients include numerous amyloid plaques, severe to absent spongiform changes, neuronal loss, astrocytic microgliosis, and variable nuerofibrillary tangles [ 28 , 29 , 59 ]. Several cases of human prion disease, since then, have been associated with iatrogenic transmission of CJD by the use of stereotactic intracerebral EEG needles or neurosurgical instruments, cadaveric dura mater grafts and intramuscular injections of contaminated cadaveric pituitary-derived human growth hormone hGH and gonadotrophin hormone.

Most of CJD cases linked to treatment with hGH have occurred in France, while those linked to treatment with dura mater grafts have mainly occurred in Japan [ 28 , 29 , 51 , 60 ]. It is believed that the likely PrP Sc contamination of pituitary-derived hGH and dura mater grafts resulted from the practice of batch processing. Before the production of recombinant hGH, it was a pharmaceutical practice to process 5,, cadaveric pituitary glands in a single batch for the extraction of the hormone. The presence in the batch of a few pituitary glands from unknown CJD cases may be responsible for contamination.

With the availability of recombinant hGH and the initiation of separated processing of individual dura mater grafts since , the probability of occurring future iCJD cases appears to be very low. A peak in the incidence of iCJD cases with long incubation periods may occur, however [ 28 , 29 , 60 ]. The MM homozygosity is a risk factor and incubation periods may be in the range of 4.

In contrast, the clinicopathological features of CJD linked to neurografting of dura mater or the use of neurosurgical instruments resemble with those of sCJD. The mean duration of illness is 18 months and the incubation periods may be in the range of 1. Kuru is the first human prion disease that was shown to be transmissible to chimpanzees by intracerebral introduction of brain homogenates from kuru patients [ 62 ]. Kuru has occurred exclusively in the Fore linguistic group of Papua New Guinea Eastern Highlands and the neighboring peoples with whom they intermarried.

There was a practice among these groups to consume the dead bodies of their relatives as a mark of respect and mourning ritualistic cannibalism. Women and young children of both sexes were more exposed to the risk material such as brain and viscera than adult men who usually had preferentially to consume muscles.


Some villages became even devoid of adult women. With a ban on ritualistic cannibalism in the mids imposed by Australian authorities, the incidence of the disease started to decline steadily. Kuru was introduced to Western medicine in late s, although the first case of kuru was observed around The Western scientists were very soon able to prove ritualistic cannibalism as the etiology of the disease.

The older kuru patients who experienced an exposure to the infection before the ban can still be seen. The incubation periods of kuru in such patients would be more than 50 years [ 27 , 59 , 63 — 65 ]. Kuru has imposed strong selection pressure in the affected Fore groups on PRNP especially at codons and Heterozygosity at these PRNP codons is a resistance factor for kuru and can be seen with marked prevalence among survivors of the kuru epidemic [ 27 , 65 ]. Kuru has 3 clinical stages namely ambulant still can walk , sedentary only can sit up , and terminal unable to sit up independently.

An ill-defined prodromal period characterized by headache and pain usually in the joints of legs may precede these stages. Cerebellar ataxia, tremors and choreiform and athetoid movements are distinctive and prominent clinical signs. Shivering amplifiable by cold was the symptom on the basis of which the disease was named "kuru".

The most prominent clinical feature of sCJD, the dementic illness can also occur in some cases but it happens during the final disease stages only. Neuropathological features such as spongiosis, neuronal loss, and astrocytic microgliosis can variably be observed in CNS usually in the grey matter. The neuropathological property which distinguishes kuru from sCJD is the presence of numerous kuru plaques, spherical bodies with a rim of radiating filaments.

Kuru is believed to be caused by the consumption of a sCJD case and experimental transmission studies have shown similarity between the molecular and pathobiological properties of prions causing kuru, sCJD and iCJD [ 66 ]. Similar studies have also revealed differences in transmission dynamics, peripheral pathogenesis and the neuropathology properties of kuru and vCJD prions.

As both kuru and vCJD are caused by infection via oral route, these differences can be attributed to the strain type rather than the route of infection [ 63 ]. However, a recent study showed that sCJD, BSE and scrapie agents were evidently different from the kuru agent in incubation time, brain neuropathology, and the lymphoreticular involvement. The authors concluded that "the geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases" [ 67 , 68 ].

The age of these patients was relatively younger between 16 and 39 years and they manifested a predominance of psychiatric symptoms instead of cerebellar ataxia or progressive dementia [ 60 ]. Psychiatric and behavioral symptoms of vCJD may include agitation, aggression, depression, anxiety, apathy, emotional lability, insomnia, poor concentration, paranoid delusion, recklessness, or withdrawal; a combination of two or more of these symptoms appears in most of the patients. Some patients may also show signs of sensory disturbance such as pain, paresthesia, and dysesthesia. The neurologic symptoms occur at least 6 months after the onset of psychiatric symptoms and include cerebellar ataxia, cognitive impairment, involuntary movements which may be dystonic, choreiform or myoclonic.

Incontinence of urine, progressive immobility, and akinetic mutism are the late onset signs. Death often occurs because of intercurrent infections. The mean age at onset of symptoms is 29 years, and the progression or total duration of the disease spans 18 months in average, which is similar to that is reported for kuru and iCJD linked to treatment with hGH [ 28 , 29 , 60 ].

However, the observation of posterior thalamic high signals characterized by 'pulvinar' or 'hockey stick' signs on T2 diffusion or Flair weighted MRI imaging and the detection of PrP res in tonsillar biopsy are important for the specific diagnosis of the disease [ 29 , 70 ]. The neuropathalogical hallmark of vCJD is the presence of kuru-type amyloid plaques surrounded by spongiform lesions "the florid plaques" which also have been seen in scrapie but never in other human prion diseases [ 28 , 29 , 60 ].

Molecular classification of sporadic Creutzfeldt–Jakob disease | Brain | Oxford Academic

Spongiform changes occur most evidently in the basal ganglia and thalamus with sparse distribution throughout the cerebral cortex. The florid plaques and PrP res immunohistochemical staining have occurred predominantly in the cerebellum and cerebrum [ 28 ]. However, sufficient amounts of PrP res are detected in the lymphoreticular system of vCJD patients [ 60 ]. The detection of PrP res in the lymphoreticular system has confidently been used for the diagnosis of vCJD even in clinically normal subjects carriers [ 71 ].

Very soon after the report on 10 vCJD cases, epidemiological studies, experimental transmission of the disease to cynomologous macaques and mice wild as well as transgenic and biochemical strain typing linked the etiology of vCJD to infection from BSE prions [ 60 ]. The same or diverse phenotypes may develop on primary and secondary transmission of vCJD and BSE to mice expressing human PrP, depending on the source of inoculum and the PrP sequence of the recipient, and the MV heterozygotes may be less resistant to vCJD transmission as compared to BSE transmission [ 73 , 74 ].

The EK heterozygosity which has been considered a risk factor for transmission of BSE to humans may confer resistance to vCJD transmission within humans [ 70 , 75 ]. Moreover, at least 4 pathologically confirmed cases including 1 with subclinical or potentially preclinical infection have been associated with the secondary vCJD transmission via blood transfusion [ 76 ]. These reports on secondary iatrogenic transmission and the possibility of vCJD occurrence with long incubation periods in individuals with MV and VV PrP genotypes have raised serious public health concerns [ 71 , 72 , 77 , 78 ].

Some cases of kuru and iCJD have occurred after incubating the disease for almost 50 and 30 years, respectively [ 63 , 64 , 76 , 79 ]. In , a novel form of atypical dementia was demonstrated in 11 patients, all of whom were VV homozygotes and most of whom revealed a positive family history for cognitive impairment. The clinical course of the disease was 2 years longer than sCJD but neuropathological profiles were diagnostic of TSEs.

A more distinctive feature based on which the disease was named initially as "protease-sensitive prionopathy" PSPr was the reduced resistance of PrP Dis isoforms to proteolysis by PK. These studies will also inform on molecular mechanisms of the disease pathogenesis. As the sensitivity of PrP Dis isoforms to treatment with PK was variable according to the codon genotype, the disease was renamed as "variably protease-sensitive prionopathy" VPSPr.

Moreover, based on the codon genotype, the PrP Dis conformers from VPSPr cases not only showed differential immunoreativity to monoclonal antibodies raised against various PrP epitopes but also varied in the intensity ratios of individual fragments. Whether the codon genotypes are associated with distinct clinical phenotypes, neuropathological lesions and histological distribution of PrP Dis remains to be elucidated.

However, sporadic and genetic cases of human prion diseases are occurring worldwide with an annual prevalence of cases per million of population. Among genetic human prion diseases, GSS presents predominantly as an amyloidopathy.

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There is no cure for these disorders. Most of developing countries including Pakistan have no epidemiological information on human prion diseases. These results indicate that Pakistani population is susceptible to prion disorders [ 84 ].

Prion Diseases and Copper Metabolism

If any nucleotide variation is found within a repeat, the name of that nucleotide is added to the name of corresponding repeat i. Physiol Rev , Prusiner SB: Prions. Nat Struct Mol Biol , Science , Aguzzi A: Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis. J Neurochem , Imran M, Mahmood S: An overview of animal prion diseases. These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins.

As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein.

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In particular, 29 of the known proteins with an RNA recognition motif also have a putative prion domain. The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of amyloid fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates. These mutations promote the misfolding of the proteins into a prion-like conformation.

The misfolded form of TDP forms cytoplasmic inclusions in afflicted neurons, and is found depleted in the nucleus. The misfolding of TDP is largely directed by its prion-like domain. As in yeast, the prion-like domain of TDP has been shown to be both necessary and sufficient for protein misfolding and aggregation. Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration.

The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.