Prion Protein Overexpression in Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Effectively Protected Rodent Kidney Against Ischemia-Reperfusion Injury Via Enhancing ATP/Mitochondrial Biogenesis-Role of ADMSC Rejuvenation and Proliferation.

BACKGROUND: We tested the hypothesis that overexpression of cellular-prion-protein in adipose-derived mesenchymal stem cells (PrPCOE-ADMSCs) effectively protected the kidney against ischemia-reperfusion (IR) injury in rat. METHODS: Part I of cell culture was categorized into A1(ADMSCs)/A2(ADMSCs+p-Cresol)/A3(PrPCOE in ADMSCs)/A4 (PrPCOE in ADMSCs+p-Cresol). Part II of cell culture was divided into B1(ADMSCs)/B2[ADMSCs+lipopolysaccharide (LPS)]/B3(PrPCOE in ADMSCs)/B4(PrPCOE in ADMSCs+LPS). Sprague-Dawley (SD) rats (n = 50) were equally categorized into groups 1 (sham-operated-control)/2 (IR)/3 (IR+ADMSCs/6.0 × 105 equally divided into bilateral-renal arteries and 6.0 × 105 intravenous administration by 1 h after IR)/4 [IR+PrPCOE-ADMSCs (identical dosage administered as group 3)]/5 [IR+silencing PRNP -ADMSCs (identical dosage administered as group 3)], and kidneys were harvested post-day 3 IR injury. RESULTS: Part I results demonstrated that the cell viability at 24/48/72 h, BrdU uptake/number of mitDNA/APT concentration/mitochondrial-cytochrome-C+ cells and the protein expressions of ki67/PrPC at 72 h-cell culturing were significantly higher in PrPCOE-ADMSCs than in ADMSCs (all P < 0.001). The protein expressions of oxidative-stress (NOX-1/NOX2/NOX4/oxidized protein)/mitochondrial-damaged (p22-phox/cytosolic-cytochrome-C)/inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers were lowest in A1/A3 and significantly higher in A2 than in A4 (all P < 0.001). Part II result showed that the protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers exhibited an identical pattern of part I among the groups (all P < 0.001). The protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized-protein)/mitochondrial-damaged (cytosolic-cytochrome-C/p22-phox)/apoptotic (cleaved caspase-3/cleaved-PARP/mitochondrial-Bx)/autophagic (beclin-1/ratio of LC3B-II/LC3B-I)/fibrotic (Smad3/TGF-ß) biomarkers and kidney-injury-score/creatinine level were lowest in group 1, highest in group 2, significantly higher in group 5 than in groups 3/4 (all P < 0.0001). CONCLUSION: PrPCOE in ADMSCs rejuvenated these cells and played a cardinal role on protecting the kidney against IR injury.

Anti-amyloid potential of some phytochemicals against Aß-peptide and α-synuclein, tau, prion, and Huntingtin protein.

Some molecules self-assemble to create complex structures through molecular self-assembly. Hydrogel preparation, tissue repair, and therapeutic drug delivery are a few applications of molecular self-assembly. However, the self-assembly of amino acids, peptides, and proteins forms amyloid fibrils, resulting in various disorders, most notably neurodegenerative ailments. Examples include the self-assembly of phenylalanine, which causes phenylketonuria; Aß, which causes Alzheimer's disease; the tau protein, which causes both Alzheimer's and Parkinson's diseases; and α-synuclein, which causes Parkinson's illness. This review provides information related to phytochemicals of great significance that can prevent the formation of, or destabilize, amino acid, peptide, and protein self-assemblies.

Prion-like mechanisms in neurodegenerative disease: Implications for Huntington's disease therapy.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansions in the huntingtin gene resulting in the synthesis of a misfolded form of the huntingtin protein (mHTT) which is toxic. The current treatments for HD are only palliative. Some of the potential therapies for HD include gene therapy (using antisense oligonucleotides and clustered regularly interspaced short palindromic repeats-Cas9 system) and stem-cell-based therapies. Various types of stem cell transplants, such as mesenchymal stem cells, neural stem cells, and reprogrammed stem cells, have the potential to either replace the lost neurons or support the existing neurons by releasing trophic factors. Most of the transplants are xenografts and allografts; however, recent reports on HD patients who received grafts suggest that the mHTT aggregates are transferred from the host neurons to the grafted cells as well as to the surrounding areas of the graft by a "prion-like" mechanism. This observation seems to be true for autotransplantation paradigms, as well. This article reviews the different types of stem cells that have been transplanted into HD patients and their therapeutic efficacy, focusing on the transfer of mHTT from the host cells to the graft. Autotransplants of reprogramed stem cells in HD patients are a promising therapeutic option. However, this needs further attention to ensure a better understanding of the transfer of mHTT aggregates following transplantation of the gene-corrected cells back into the patient.

Prionpatías: las encefalopatías por priones / Prion diseases: prion encephalopathies

Las prionpatías o encefalopatías por priones son un grupo de enfermedades poco frecuentes que comparten una fisiopatología similar con distintas características clínicas. La enfermedad de Creutzfeldt-Jakob (ECJ) esporádica es la más conocida. Se manifiesta con una demencia rápidamente progresiva, ataxia y sintomatología extrapiramidal. Aunque el diagnóstico de certeza es anatomopatológico se puede llegar al diagnóstico probable empleando los criterios establecidos por la Organización Mundial de la Salud. Se está discutiendo en la actualidad la posibilidad de integrar la resonancia magnética nuclear en dichos criterios para aumentar la sensibilidad del diagnóstico. Las técnicas moleculares de estudio de proteínas en el líquido cefalorraquídeo tienen un peso creciente y colaboran en el diagnóstico. El diagnóstico de las otras encefalopatías por priones no es tan avanzado como el de la ECJ. El tratamiento de todas estas enfermedades continúa siendo paliativo (AU)

Prion diseases or prion encephalopathies are a group of rare disorders that share a similar pathophysiology with different clinical characteristics. Sporadic Creutzfeldt-Jakob disease (CJD) is best known. It presents as a rapidly progressive dementia, ataxia and extrapyramidal symptoms. Although accurate diagnosis is by histopathological examination, a diagnosis can be probably achieved using the criteria established by the World Health Organization. We are currently discussing the possibility of integrating the nuclear magnetic resonance into this criteria for increasing the sensitivity of diagnosis. Molecular techniques for studying proteins in cerebrospinal fluid have an increasingly significant role in aiding diagnosis. The diagnosis of other prion encephalopathies is not as advanced as that of CJD. The treatment of these diseases remains palliative (AU)

Polylactide-coglycolide microspheres co-encapsulating recombinant tandem prion protein with CpG-oligonucleotide break self-tolerance to prion protein in wild-type mice and induce CD4 and CD8 T cell responses.

Prion diseases are fatal neurodegenerative diseases that are characterized by the conformational conversion of the normal, mainly alpha-helical cellular prion protein (PrP) into the abnormal beta-sheet-rich infectious isoform (PrP(Sc)). The immune system neither shows reaction against cellular PrP nor PrP(Sc), most likely due to profound self-tolerance. In previous studies, we were able to partly overcome self-tolerance using recombinantly expressed dimeric PrP (tandem PrP (tPrP)), in association with different adjuvants. Proof of principle for antiprion efficacy was obtained in vitro and in vivo. In this study, we demonstrate the induction of a specific Th1 T cell response in wild-type mice immunized with tPrP and CpG-oligonucleotide (ODN). Biochemical influences such as refolding conditions, ionic strength, pH, and interaction with CpG-ODN affected antigenic structure and thus improved immunogenicity. Furthermore, s.c. immunization with tPrP and CpG-ODN co-encapsulated in biodegradable polylactide-coglycolide microspheres (PLGA-MS) enhanced CD4 T cell responses and, more prominent, the induction of CD8 T cells. In this vaccination protocol, PLGA-MS function as endosomal delivery device of Ag plus CpG-ODN to macrophages and dendritic cells. In contrast, PLGA-MS-based DNA vaccination approaches with a tPrP construct generated poor humoral and T cell responses. Our data show that prophylactic and therapeutic immunization approaches against prion infections might be feasible using tPrP Ag and CpG-ODN adjuvant without detectable side effects.

Progress in prion vaccines and immunotherapies.

The transmissible spongiform encephalopathies have presented a challenge to physicians and scientists attempting to develop immunologically-based treatments. Self-tolerance has been one of the major obstacles to successfully raising antibodies against the prion protein (PrP), the host-encoded protein whose misfolded form (PrPSc) is linked to the protein-only infectious agent responsible for these disorders. Recently, it has been shown that antibodies directed against the normal cellular isoform of PrP (PrPC) can reduce or eliminate PrP isoform conversion in both in vitro and in vivo model systems. Similar studies with a PrPSc-specific epitope target are in progress. There is now rational hope that this devastating group of diseases may soon be amenable to immunotherapy and immunoprophylaxis.

Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent.

Several lines of evidence suggest that immunisations may be helpful in the prophylaxis and treatment of neurodegenerative amyloidoses like Alzheimer's disease and prion infections. We used a synthetic prion protein-derived peptide (PrP105-125) and a recombinant PrP fragment (PrP90-230) as antigens for the active immunisation of mice, which were subsequently infected by dietary exposure to the scrapie agent. Immunisation with PrP105-125 prolonged the survival times significantly. In contrast, immunisation with PrP90-230 or adjuvants alone had no effect on the disease development. An epitope mapping of the antibodies raised against PrP90-230 revealed that reactivities against previously defined protective epitopes were either underrepresented or absent. These results point towards the possibility to prevent prion spread via the food chain by vaccinating humans or other species at risk to contract prion diseases.

Immunization treatment approaches in Alzheimer's and prion diseases.

There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans.