The effect of TRIM5 variants on the susceptibility to HIV-1 infection and disease progression in the Polish population.

BACKGROUD: Tripartite motif containing 5α protein is a factor contributing to intracellular defense mechanisms against human immunodeficiency virus-1 (HIV-1) infection. The studies of TRIM5 variants effects on the risk of HIV-1 infection and the clinical course of disease provided inconclusive results in different ethnic groups. The aim of this study was to investigate the influence of TRIM5 variants on susceptibility to HIV-1 infection and clinical parameters among Polish HIV-1-infected patients. MATERIALS & METHODS: In our study, we investigated 301 HIV-1-infected patients and 186 age-matched seronegative controls. Seven variants of the TRIM5 gene (rs7127617, rs3824949, rs3740996, rs11601507, rs10838525, rs11038628, and rs28381981) were genotyped using both sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. RESULTS AND CONCLUSIONS: The frequencies of rs7127617 TT genotype and T allele occurrence were lower in HIV-1-infected subjects compared to controls (0.14 vs. 0.26 for T/T genotype and 0.45 vs. 0.54 for T allele), suggesting their possible protective effect (p = 0.005 and p = 0.007, respectively). Heterozygosity and presence of the T allele at rs3740996 were enriched in controls compared to HIV-1-infected group (0.19 vs. 0.12 for C/T genotype and 0.11 vs. 0.07 for T allele; p = 0.03 and p = 0.02, respectively). Moreover, rs3824949 CC genotype carriers had a lower viral load than patients bearing rs3824949 GG/CG genotypes (4.0 vs. 4.6 log copies/mL; p = 0.049); however, none of the variants affected CD4+ cell count. In conclusion, our data confirm the role of TRIM5 variants in the HIV-1 transmission and the clinical course of HIV-1 infection. The presence of rs7127617 TT genotype and T allele seems to protect against HIV-1 transmission in examined population.

From Alpha to Delta-Genetic Epidemiology of SARS-CoV-2 (hCoV-19) in Southern Poland.

In Poland, the first case of SARS-CoV-2 infection was confirmed in March 2020. Since then, many circulating virus lineages fueled rapid pandemic waves which inflicted a severe burden on the Polish healthcare system. Some of these lineages were associated with increased transmissibility and immune escape. Mutations in the viral spike protein, which is responsible for host cell recognition and serves as the primary target for neutralizing antibodies, are of particular importance. We investigated the molecular epidemiology of the SARS-CoV-2 clades circulating in Southern Poland from February 2021 to August 2021. The 921 whole-genome sequences were used for variant identification, spike mutation, and phylogenetic analyses. The Pango B.1.1.7 was the dominant variant (n = 730, 89.68%) from March 2021 to July 2021. In July 2021, the B.1.1.7 was displaced by the B.1.617.2 lineage with 66.66% in July 2021 and 92.3% in August 2021 frequencies, respectively. Moreover, our results were compared with the sequencing available on the GISAID platform for other regions of Poland, the Czech Republic, and Slovakia. The analysis showed that the dominant variant in the analyzed period was B.1.1.7 in all countries and Southern Poland (Silesia). Interestingly, B.1.1.7 was replaced by B.1.617.2 earlier in Southern Poland than in the rest of the country. Moreover, in the Czech Republic and Slovakia, AY lineages were predominant at that time, contrary to the Silesia region.

Neuro-COVID-19: an insidious virus in action.

INTRODUCTION: The punishing effect of the pandemic outbreak of the disease termed COVID-19 (coronavirus disease-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) impelled the author to gather the facts about the nature of this new pathogen. The aim of this paper was to discuss the mechanisms involved in the pathogenesis of neurological complications during the course of COVID-19. STATE OF THE ART: Neurological symptoms, such as impairment of taste or smell, headache, nausea and/or altered consciousness, are commonly described in COVID-19 patients, although there are emerging clinical reports of more serious conditions such as acute cerebrovascular accidents, encephalitis and demyelinating disease. Whether these manifestations are the direct consequence of viral invasion of the central nervous system, or are caused by indirect mechanisms, is yet to be established. Studies to date have indicated that neurological lesions found in the brains of COVID-19 patients are a combination of direct cytopathic effects caused by SARS-CoV-2 replication and indirect effects due to hypoxia, excessive cytokine reaction, impaired immune response, and cerebrovascular injury induced by viral infection. Studies are still pending into possible routes of SARS-CoV-2 neuroinvasion encompassing the haematopoietic pathway via the blood-brain barrier and retrograde axonal transport through the cranial nerves. CLINICAL IMPLICATIONS: A thorough understanding of SARS-CoV-2 involvement in neurological complications is still lacking. However, our knowledge about SARS-CoV-2 virulence is rapidly expanding, and that has inclined the author to prepare this comprehensive review in the hope that it will improve understanding about the molecular mechanisms underlying neurological abnormalities associated with COVID-19. FUTURE DIRECTIONS: A future detailed study should explore the diagnostics and disease mechanisms so as to enable the development of better therapeutic strategies to reduce the severity of COVID-19 neurological complications.

Does Virus-Receptor Interplay Influence Human Coronaviruses Infection Outcome?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the third (following SARS-CoV and Middle East Respiratory Syndrome-CoV) zoonotic coronavirus that has crossed the species barrier in the 21st century, resulting in the development of serious human infection. The punishing effect of the recent outbreak of pandemic disease termed COVID-19 (coronavirus disease-19) caused by SARS-CoV-2 impelled us to gather the facts about the nature of coronaviruses. First, we introduce the basic information about coronavirus taxonomy, structure, and replication process to create the basis for more advanced consideration. In the following part of this review, we focused on interactions between the virus and the receptor on the host cell, as this stage is the critical process determining the species and tissue tropism, as well as clinical course of infection. We also illuminate the molecular basis of the strategy used by coronaviruses to cross the species barrier. We give special attention to the cellular receptor's interaction with S protein of different CoVs (dipeptidyl peptidase IV and angiotensin-converting enzyme 2), as well as the cellular proteases involved in proteolysis of this protein. These factors determine the virus entry and replication; thus, even fine quantitative or qualitative differences in their expression may crucially affect outcomes of infection. Understanding virus biology and characterization of the host factors involved in coronavirus transmission and pathogenesis may offer novel options for development of efficient therapeutic and preventive strategies.

Transmission patterns of HIV-1 non-R5 strains in Poland.

HIV-1 env sequencing enables predictions of viral coreceptor tropism and phylogenetic investigations of transmission events. The aim of the study was to estimate the contribution of non-R5 strains to the viral spread in Poland. Partial proviral env sequences were retrieved from baseline blood samples of patients with newly diagnosed HIV-1 infection between 2008-2014, including 46 patients with recent HIV-1 infection (RHI), and 246 individuals with long-term infection (LTHI). These sequences were subjected to the genotypic coreceptor tropism predictions and phylogenetic analyses to identify transmission clusters. Overall, 27 clusters with 57 sequences (19.5%) were detected, including 15 sequences (26.3%) from patients with RHI. The proportion of non-R5 strains among all study participants was 23.3% (68/292), and was comparable between patients with RHI and LTHI (11/46, 23.9% vs 57/246, 23.2%; p = 1.000). All 11 patients with non-R5 strains and RHI were men having sex with men (MSM). Among these patients, 4 had viral sequences grouped within phylogenetic cluster with another sequence of non-R5 strain obtained from patient with LTHI, indicating potential acquisition of non-R5 HIV-1 for at least 4/46 (8.7%) patients with RHI. We were unable to confirm the contribution of patients with RHI to the forward transmission of non-R5 strains, but a relatively high proportion of non-R5 strains among them deserves attention due to the limited susceptibility to CCR5 antagonists.

Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene as risk factors for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a complex aetiology. The ε4 allel of the apolipoprotein E gene (APOE) is the only confirmed genetic risk factor for the development of AD. In addition, polymorphisms at the promoter region of the APOE gene are assumed to modulate the susceptibility to AD by their different affinity to the transcription factors thus affecting the expression of the gene. In the presented study, we investigated the association between -491 A/T (rs449647), -427C/T, (rs769446) and -219 T/G (rs405509) single nucleotide polymorphisms (SNPs) of APOE gene and AD risk in the Polish population. We found that only the -491 T allele and -491 A/T genotype acted as protective factors against AD, whereas the -219 T/G heterozygosity increased risk for AD in APOE ε4 carriers but not in APOE ε4 non-carriers. What is more, haplotype frequency estimation showed significant positive for A-T-T-C-C and A-T-G-C-C haplotypes or negative for A-T-T-T-C and T-T-T-T-C haplotypes associations with AD. These results contribute to the evidence that APOE promoter polymorphisms modulate risk for AD.

Vancomycin and/or Multidrug-Resistant Citrobacter Freundii Altered the Metabolic Pattern of Soil Microbial Community.

Despite many studies, our knowledge on the impact of antibiotics and antibiotic-resistant bacteria on the metabolic activity of soil microbial communities is still limited. To ascertain this impact, the community level physiological profiles (CLPPs) and the activity of selected enzymes (dehydrogenase, urease, and phosphatases) in soils treated with vancomycin (VA) and/or multidrug resistant Citrobacter freundii were determined during a 90-day experiment. A multivariate analysis and the resistance (RS)/resilience (RL) concept were used to assess the potential of native microorganisms to maintain their catabolic activity under exposure of VA and/or a high level of C. freundii. In addition, the dissipation rate of VA was evaluated in non-sterile (nsS) and sterile (sS) soils. The results revealed a negative impact of VA on the metabolic activity of soil microorganisms on days 1, 15, and 30 as was showed by a decrease in the values of the CLPP indices (10-69%) and the enzyme activities (6-32%) for treated soils as compared to the control. These observations suggested a low initial resistance of soil microorganisms to VA and/or C. freundii but they were resilient in the long term. Considering the mean values of the RS index, the resistance of measured parameters was categorized in the following order: alkaline phosphatase (0.919) > acid phosphatase (0.899) > dehydrogenase (0.853) > the evenness index (0.840) > urease (0.833) > the Shannon-Wiener index (0.735) > substrate richness (0.485) > the AWCD (0.301). The dissipation process of VA was relatively fast and independent of the concentration used. The DT50 values for VA applied at both concentrations were about 16 days. In addition, the dissipation of VA in nsS was three times faster compared to the dissipation of antibiotic in sS. In conclusion, both CLPP and enzyme activities assays appeared to be useful tool for the determination of disturbances within soil microbial communities and used together may be helpful to understand the changes in their catabolic features. The entry of large quantities of VA and/or C. freundii into soil may temporarily change microbial activity thus pose a potential risk for soil functioning.

HIV-1 Infection in Persons Homozygous for CCR5-Δ32 Allele: The Next Case and the Review.

CC-chemokine receptor 5 serves as the coreceptor for the HIV-1 R5 strains, which are responsible for the majority of HIV transmissions. A deletion of 32 nucleotides in the gene encoding this receptor (termed CCR5-Δ32) leads to the suppression of CC-chemokine receptor 5 presentation at the cell surface, thus impeding process of HIV entry into the cell. Individuals homozygous for the CCR5-Δ32 allele are resistant to infection with HIV-1 R5 strains, and are extremely rare among HIV-1-infected individuals. We have described a case of person homozygous for CCR5-Δ32, who was infected with subtype B HIV-1. Based on examination of proviral V3 sequences obtained from the first clinical blood sample within less than five months after seroconversion, the CXC-chemokine receptor 4-using strains (X4 or R5/X4) were detected. Data on HIV-1-infected patients homozygous for the CCR5-Δ32 allele, course of HIV-1 infection in these cases, and the infecting viral strains from current and all former reports on HIV-1 infection in CCR5-Δ32 homozygotes were gathered and compared. Identification of HIV-1-infected persons homozygous for CCR5-Δ32 supports the evidence that the lack of functional CC-chemokine receptor 5 at the cell surface does not confer absolute protection against HIV-1 infection, which should be considered when designing future HIV pre-exposure prophylaxis schemes basing on CC-chemokine receptor 5 blocking drugs.

Prevalence of Transmitted Drug-Resistance Mutations and Polymorphisms in HIV-1 Reverse Transcriptase, Protease, and gp41 Sequences Among Recent Seroconverters in Southern Poland.

BACKGROUND Monitoring of drug resistance-related mutations among patients with recent HIV-1 infection offers an opportunity to describe current patterns of transmitted drug resistance (TDR) mutations. MATERIAL AND METHODS Of 298 individuals newly diagnosed from March 2008 to February 2014 in southern Poland, 47 were deemed to have recent HIV-1 infection by the limiting antigen avidity immunoassay. Proviral DNA was amplified and sequenced in the reverse transcriptase, protease, and gp41 coding regions. Mutations were interpreted according to the Stanford Database algorithm and/or the International Antiviral Society USA guidelines. TDR mutations were defined according to the WHO surveillance list. RESULTS Among 47 patients with recent HIV-1 infection only 1 (2%) had evidence of TDR mutation. No major resistance mutations were found, but the frequency of strains with ≥1 accessory resistance-associated mutations was high, at 98%. Accessory mutations were present in 11% of reverse transcriptase, 96% of protease, and 27% of gp41 sequences. Mean number of accessory resistance mutations in the reverse transcriptase and protease sequences was higher in viruses with no compensatory mutations in the gp41 HR2 domain than in strains with such mutations (p=0.031). CONCLUSIONS Despite the low prevalence of strains with TDR mutations, the frequency of accessory mutations was considerable, which may reflect the history of drug pressure among transmitters or natural viral genetic diversity, and may be relevant for future clinical outcomes. The accumulation of the accessory resistance mutations within the pol gene may restrict the occurrence of compensatory mutations related to enfuvirtide resistance or vice versa.

Transmission of drug-resistant HIV-1 variants among individuals with recent infection in southern Poland.

Transmitted drug resistance (TDR) is an important public health issue, because it may affect the outcome of antiretroviral treatment. The prevalence of human immunodeficiency virus type 1 (HIV-1) with TDR mutations defined according to the list of the World Health Organization was investigated among 53 therapy-naïve persons with confirmed recent HIV-1 infection diagnosed in Poland, in the years 2008-2010. Proviral DNA was amplified, sequenced, and screened for the TDR mutations in the pol gene fragments coding for the whole protease and the initial 256 residues of the reverse transcriptase. The frequency of sequences with at least one TDR mutation was 11.3%. In four (7.5%) sequences at least one resistance mutation related to reverse transcriptase inhibitors was identified, and in further two (3.8%) sequences one mutation related to protease inhibitors' resistance was present. The moderate rate of TDR highlights the need for a continuous surveillance and resistance testing among treatment-naïve individuals to optimize treatment effects within a country.

Molecular epidemiology of recent HIV-1 infections in southern Poland.

The genetic diversity of human immunodeficiency virus type 1 (HIV-1) offers an opportunity to track the development of the epidemic across different populations. Viral pol gene fragments from 55 individuals of Polish origin with recent HIV-1 infection identified in 2008-2010 in four Polish cities were analyzed. Viral sequences were compared with sequences from 100 individuals (reference group) infected before 2004. Viral spread among groups with different HIV transmission categories was compared using a phylogenetic approach. The majority of sequences from individuals with recent infection were subtype B (93%) within which four transmission clusters (18% of samples) were detected. Samples from men infected through sex between men and from persons infected through injecting drugs were broadly separated (P < 0.0001), while samples from individuals infected by heterosexual contacts were dispersed uniformly within phylogenetic tree (P = 0.244) inferred from viral sequences derived from individuals infected recently and the reference group. The percentage of samples from persons infected by heterosexual contacts which clustered with samples from men infected through sex between men was not significantly higher for those with recent infection (47%), compared to the reference group (36%). In conclusion, men infected by sex between men and individuals infected through injecting drugs appear to form separate HIV transmission networks in Poland. The recent spread of HIV-1 among persons infected with subtype B by heterosexual contacts appears to be linked to both these groups.

Association between the PRNP 1368 polymorphism and the occurrence of sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. The etiology of sporadic form of CJD remains unsolved. In addition to the codon 129 polymorphism, polymorphisms in the non-coding region of PRNP are considered as important factors in sCJD development. To assess a possible association between PRNP 1368 SNP and sCJD, we compared the genotype, allele and haplotype frequencies of the 1368 SNP among 46 sCJD patients of Dutch origin with the respective frequencies in healthy controls. We detected a significant association between sCJD and 1368T/T genotype. A significant difference was also observed in 1368 alleles' distribution. In the haplotype analysis, haplotype 1368C-129G was associated with decreased risk of sCJD in Dutch population. Our findings support the hypothesis that genetic variations in the regulatory region of the PRNP gene may influence the pathogenesis of sCJD.

Association of the PRNP regulatory region polymorphisms with the occurrence of sporadic Creutzfeldt-Jakob disease.

The prion protein (PrP) plays a central role in the pathogenesis of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies (TSEs). Mutations in the coding region of the prion protein (PRNP) gene are linked to inherited forms of TSEs whereas aetiology of sporadic CJD (sCJD) remains obscure. It remains unclear whether the primary DNA sequence at non-coding region of PRNP gene influences development of the sCJD. Several recent reports showed non-coding region polymorphisms associated with sCJD but other could not support those findings. To test the hypothesis that there is a relationship between SNPs polymorphisms of PRNP non-coding regions and susceptibility to sCJD, we compared the primary structure of the regulatory region of the PRNP in 45 Dutch sCJD patients and in 135 healthy controls. We found a significant linkage of +310 C allele (OR 0.27, 95% CI 0.09-0.77; P = 0.009) and +310G/C genotype (OR 0.33, 95% CI 0.11-0.98; P = 0.048) with sCJD. No differences in frequencies of genotypes and allele of -101C/G and +258 G/A polymorphisms were found between sCJD patients and controls. We found two haplotypes protecting from sCJD (C-V in block 1 and G-C in block 2) and one susceptible haplotype for sCJD (G-G in block 2). Our findings support the hypothesis that polymorphism in the regulatory region of the PRNP gene may play an important role in the pathogenesis of sCJD.

Retrospective analysis of the HIV-1 reverse transcriptase inhibitors' resistance in Silesia, Poland.

BACKGROUND: This study was a retrospective analysis of drug resistance mutations among HIV-1 strains prevalent in Silesia, Poland, from the origin of the epidemic to 2004. The investigations included both type and frequency of the reverse transcriptase inhibitors' resistance mutations and estimation of the drugs' resistance levels. MATERIAL/METHODS: Proviral DNA, obtained from peripheral blood mononuclear cells of the 101 HIV-1-infected patients, was amplified and sequenced in the pol gene fragment covering the first 256 codons of the reverse transcriptase (RT). Reverse transcriptase inhibitors resistance mutations were determined and interpreted with the HIVdb: Genotypic Resistance Interpretation Algorithm available from the Stanford University HIV Drug Resistance Database. In the examined population, 35 subjects (34.7%) received no antiretroviral treatment by the time of specimen collection. RESULTS: The overall frequency of the RT inhibitors resistance mutations in the studied population was 15.8%. Substitutions related to the reverse transcriptase inhibitors resistance were identified in 10 pol gene sequences (9.9%), all of them were present in the HIV-1 sequences obtained from persons receiving antiretroviral therapy. CONCLUSIONS: Lack of drug-resistant viruses among treatment-naïve Silesian patients HIV-1-infected before the year 2004 may indicate that there was no transmission of the drug-resistant viruses in the studied population to that time.

HIV type 1 genetic diversity in Silesia, Poland: a retrospective analysis.

To characterize the genetic diversity of HIV-1 strains circulating among patients with different transmission risk behaviors in Silesia, Poland, from the origin of the epidemic to the year 2004, we have sequenced and analyzed the p24 coding region of the gag gene and part of the pol gene covering the first 256 codons for the reverse transcriptase (RT). The proviral DNA was obtained from the 101 HIV-1-infected patients, 80 of whom (79.2%) were intravenous drug users (IDUs) and 21 of whom (20.8%) reported sexual transmission risk practices (STs) with 11 (10.9%) being heterosexuals and 10 (9.9%) being homosexual men, which corresponds to the population's epidemiological data. All of the investigated viral sequences were classified as HIV-1 subtype B with low genetic heterogeneity. There was an association between HIV-1 genetic diversity and the risk of virus transmission in the investigated population. The mean nucleotide distances were significantly lower among sequences derived from IDUs than among sequences obtained from STs. Additionally, strains present among IDUs, as opposed to viruses circulating among STs, were genetically more distinct from HIV-1 subtype B strains found in other populations worldwide. Our findings that HIV-1 strains circulating among IDUs were closely related to each other, but were distinct from viruses prevalent in other geographic regions, allow further tracing of the spread of these strains.

Regulatory sequences of the PRNP gene influence susceptibility to sporadic Creutzfeldt-Jakob disease.

The prion diseases are fatal neurodegenerative disorders that afflict both humans and animals. They comprise kuru, Creutzfeldt-Jakob disease (CJD), Gerstmman-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). Both GSS, FFI and approximately 10% of CJD cases are genetically linked disorders, whereas 90% of CJD cases are not associated with mutations in the PRNP coding region, therefore other factors must be involved in pathogenesis of these forms of CJD. There is strong evidence that in transgenic mice the level of PrP gene expression influences the initiation and progression of the prion diseases. Moreover, in in vitro experiments demonstrated that mutations in the regulatory region of PRNP gene altered gene expression, therefore it may be expected that PrP expression level influences the susceptibility to CJD. In order to investigate whether single nucleotide polymorphisms within regulatory region of PRNP may modulate genetic susceptibility to sporadic CJD we examined an association of the C/G polymorphism at position -101 with the sCJD. In our study -101G polymorphism is over-represented among sCJD PRNP codon 129M/V cases compared with the control group. Our data suggest that polymorphism at position -101 in the regulatory region of PRNP may be a risk factor for sCJD among codon 129 heterozygotes.

[Effects of CCR5-delta32, CCR2-64I and SDF-1-3'A polymorphic alleles on human immunodeficiency virus 1 (HIV-1) infection in the Polish population]. / Rola polimorficznych alleli CCR5-delta32, CCR2-64I i SDF-1-3'A w zakazeniu ludzkim wirusem uposledzenia odpornosci typu 1 (HIV-1) w populacji polskiej.

Among many factors that can influence vulnerability to infection and disease progression are genetic host factors together with the phenotype/genotype of the transmitting virus and the route of infection. Each of these factors alone or in combination could determine susceptibility to infection and subsequent rate of progression towards AIDS. Between host genetic factors identified and analyzed for their role in HIV-1 transmission and disease progression are polymorphisms in the genes encoding chemokine receptors and CCR5, CCR2 and SDF-1 a natural ligand for CXCR4 receptor. It has been shown that the distribution of this genetic polymorphisms and their role in the course of disease varies between different racial, ethnic and risk groups. The aim of present study was to examine the frequencies of polymorphic alleles CCR5-delta32, CCR2-64I and SDF-1-3'A and their role in human immunodeficiency virus (HIV-1) transmission in Polish population. The allelic and genotype distribution was studied in 103 HIV-1 infected patients (group HIV+) and 59 seronegative participants (group HIV-). Genotyping was done by the use of polymerase chain reaction with sequence-specific primers and restriction fragment length polymorphism. We found higher prevalence of CCR5-delta32 mutant allele among seronegative participants (13.6%) compared with HIV-infected patients (9.7%), although this did not attain statistical significance (p = 0.29). The CCR2-64I allelic frequency was almost identical in the HIV- and HIV+ groups (12.7% vs. 12.6%; respectively; p = 0.98). In contrast, the SDF-1-3'A allelic frequency was slightly lower among seronegative participants (15.3%) compared with HIV-infected patients (16.5%), and observed difference was not statistically significant (p = 0.77). Furthermore, we found that the genotype or allelic frequencies among HIV-1 infected patients were independent on the participant's sex, age at HIV-1 infection and the transmission route. Our results showed no significant differences in the prevalence of examined alleles and genotypes between HIV-1 infected patients and seronegative participants, which indicates that in the examined population they are not influencing host susceptibility to the HIV-1 infection.

Molecular approaches to mechanisms of prion diseases.

Prion diseases such as scrapie in sheep, bovine spongiform encephalopathy in cattle, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia in man are neurodegenerative disorders. In humans, the diseases can be sporadic, inherited, or acquired by infection. The underlying pathogenic event in prion diseases is a conformational modification of the cellular isoform prion protein (PrP(C)) to the pathogenic isoform (PrP(SC)) that accumulates in the central nervous system. However, in humans, in some inherited cases the pathological PrP is not PrP(Sc), but a transmembrane form of prion protein, (Ctm)PrP. Prion protein is encoded by the cellular gene, PRNP, which has been mapped to human chromosome 20p21. Familial prion diseases are thought to result from a change in structure of the prion protein produced by the mutated PRNP gene. Furthermore, polymorphic codon 129 of the PRNP gene encodes either methionine or valine and appears to influence the susceptibility of patients to iatrogenic and sporadic CJD as well as the neuropathological phenotype in these forms of CJD. Polymorphisms in the promoter region of PRNP gene or disturbances in prion protein metabolism, such as incorrect activity of cellular chaperones or proteasomes are considered as susceptibility factors in human prion diseases.

Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy.

Neuronal autophagy, like apoptosis, is one of the mechanisms of the programmed cell death (PCD). In this review, we summarize the presence of autophagic vacuoles in experimentally induced scrapie, Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Initially, a part of the neuronal cytoplasm was sequestrated by concentric arrays of double membranes; the enclosed cytoplasm appeared relatively normal except that its density was often increased. Next, electron density of the central area dramatically increased. The membranes then proliferated within the cytoplasm in a labyrinth-like manner and the area sequestrated by these membranes enlarged into a more complex structure consisting of vacuoles, electron-dense areas and areas of normally-looking cytoplasm connected by convoluted membranes. Of note, autophagic vacuoles form not only in neuronal perikarya but also in neurites and synapses. Finally, a large area of the cytoplasm was transformed into a collection of autophagic vacuoles of different sizes. On a basis of ultrastructural studies, we suggest that autophagy plays a major role in transmissible spongiform encephalopathies (TSEs) and may even participate in a formation of spongiform change.