RESUMEN
The clinical effect of human Mesenchymal stem cells (hMSCs) transplanted into EAE mice/MS patients is short lived due to poor survival of the transplanted cells. Since Granagard, a nanoformulation of pomegranate seed oil, extended the presence of Neuronal Stem cells transplanted into CJD mice brains, we tested whether this safe food supplement can also elongate the survival of hMSCs transplanted into EAE mice. Indeed, pathological studies 60 days post transplantation identified human cells only in brains of Granagard treated mice, concomitant with increased clinical activity. We conclude that Granagard may prolong the activity of stem cell transplantation in neurological diseases.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Esclerosis Múltiple , Humanos , Animales , Ratones , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patología , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/patología , Encéfalo/patología , Trasplante de Células Madre , Factores Inmunológicos , Células Madre Mesenquimatosas/patología , Células Madre Mesenquimatosas/fisiologíaRESUMEN
Traumatic Brain Injury (TBI), is one of the most common causes of neurological damage in young populations. It is widely considered as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's (PD) disease. These diseases are characterized in part by the accumulation of disease-specific misfolded proteins and share common pathological features, such as neuronal death, as well as inflammatory and oxidative damage. Nano formulation of Pomegranate seed oil [Nano-PSO (Granagard TM)] has been shown to target its active ingredient to the brain and thereafter inhibit memory decline and neuronal death in mice models of AD and genetic Creutzfeldt Jacob disease. In this study, we show that administration of Nano-PSO to mice before or after TBI application prevents cognitive and behavioral decline. In addition, immuno-histochemical staining of the brain indicates that preventive Nano-PSO treatment significantly decreased neuronal death, reduced gliosis and prevented mitochondrial damage in the affected cells. Finally, we examined levels of Sirtuin1 (SIRT1) and Synaptophysin (SYP) in the cortex using Western blotting. Nano-PSO consumption led to higher levels of SIRT1 and SYP protein postinjury. Taken together, our results indicate that Nano-PSO, as a natural brain-targeted antioxidant, can prevent part of TBI-induced damage.
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Enfermedad de Alzheimer , Lesiones Traumáticas del Encéfalo , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Cognición , Ratones , Aceites de Plantas/química , Sirtuina 1/metabolismoRESUMEN
Advanced age is the main risk factor for the manifestation of late onset neurodegenerative diseases. Metformin, an anti-diabetic drug, was shown to extend longevity, and to ameliorate the activity of recognized aging hallmarks. Here, we compared the clinical, pathologic and biochemical effects of Metformin to those of Nano-PSO (Granagard), a brain targeted anti-oxidant shown by us to delay disease advance in transgenic mice mimicking for genetic Creutzfeldt Jacob disease (CJD) linked to the E200KPrP mutation. We demonstrate that both Metformin and Nano-PSO reduced aging hallmarks activities such as activated AMPK, the main energy sensor of cells as well as Nrf2 and COX IV1, regulators of oxidation, and mitochondrial activity. Both compounds reduced inflammation and increased stem cells production, however did not decrease PrP accumulation. As opposed to Nano-PSO, Metformin neither delayed clinical disease advance in these mice nor reduced the accumulation of sulfated glycosaminoglycans, a pathologic feature of prion disease. We conclude that elevation of anti-aging markers may not be sufficient to delay the fatal advance of genetic CJD.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/prevención & control , Metformina/farmacología , Metformina/uso terapéutico , Aceites de Plantas/farmacología , Aceites de Plantas/uso terapéutico , Adenilato Quinasa/metabolismo , Animales , Antioxidantes , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Ratones , Ratones Transgénicos , Mutación , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismoRESUMEN
gCJD is a fatal late-onset neurodegenerative disease linked to mutations in the PRNP gene. We have previously shown that transplantation of neural precursor cells (NPCs), or administration of a nanoformulation of pomegranate seed oil (Nano-PSO, GranaGard), into newborn asymptomatic TgMHu2ME199K mice modeling for E200K gCJD significantly delayed the advance of clinical disease. In the present study, we tested the individual and combined effects of both treatments in older and sick TgMHu2ME199K mice. We show that while transplantation of NPCs at both initial (140 days) and advance clinical states (230 days) arrested disease progression for about 30 days, after which scores rapidly climbed to those of untreated Tgs, administration of Nano-PSO to transplanted TgMHu2ME199K mice resulted in detention of disease advance for 60-80 days, followed by a slower disease progression thereafter. Pathological examinations demonstrated the combined treatment extended the survival of the transplanted NPCs, and also increased the generation of endogenous stem cells. Our results suggest that administration of Nano-PSO may increase the beneficial effects of NPCs transplantation.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/terapia , Nanoestructuras/administración & dosificación , Células-Madre Neurales/trasplante , Aceites de Plantas/administración & dosificación , Granada (Fruta)/química , Animales , Síndrome de Creutzfeldt-Jakob/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ratones Transgénicos , Aceites de Plantas/aislamiento & purificación , Factores de TiempoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is associated with the onset of neurodegenerative diseases, such as Alzheimer's disease (AD). Conjugated Linoleic Acid (CLA), a calpain inhibitor, is a metabolite of Punicic Acid (PA), the main component of Pomegranate seed oil (PSO). We have shown recently that long-term administration of Nano-PSO, a nanodroplet formulation of PSO, delays mitochondrial damage and disease advance in a mouse model of genetic Creutzfeldt Jacob disease (CJD). In this project, we first demonstrated that treatment of mice with Nano-PSO, but not with natural PSO, results in the accumulation of CLA in their brains. Next, we tested the cognitive, biochemical and pathological effects of long-term administration of Nano-PSO to 5XFAD mice, modeling for Alzheimer's disease. We show that Nano-PSO treatment prevented age-related cognitive deterioration and mitochondrial oxidative damage in 5XFAD mice. Also, brains of the Nano-PSO treated mice presented reduced accumulation of Aß and of p25, a calpain product, and increased expression of COX IV-1, a key mitochondrial enzyme. We conclude that administration of Nano-PSO results in the brain targeting of CLA, and suggest that this treatment may prevent/delay the onset of neurodegenerative diseases, such as AD and CJD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Glicoproteínas/administración & dosificación , Ácidos Linoleicos Conjugados/administración & dosificación , Memoria/efectos de los fármacos , Aceites de Plantas/administración & dosificación , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Calpaína/antagonistas & inhibidores , Calpaína/metabolismo , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Fosfotransferasas/metabolismo , Aceites de Plantas/química , Presenilina-1/genéticaRESUMEN
Mitochondrial malfunction is a common feature in advanced stages of neurodegenerative conditions, as is the case for the accumulation of aberrantly folded proteins, such as PrP in prion diseases. In this work, we investigated mitochondrial activity and expression of related factors vis a vis PrP accumulation at the subclinical stages of TgMHu2ME199K mice, modeling for genetic prion diseases. While these mice remain healthy until 5-6â¯months of age, they succumb to fatal disease at 12-14â¯months. We found that mitochondrial respiratory chain enzymatic activates and ATP/ROS production, were abnormally elevated in asymptomatic mice, concomitant with initial accumulation of disease related PrP. In parallel, the expression of Cytochrome c oxidase (COX) subunit IV isoform 1(Cox IV-1) was reduced and replaced by the activity of Cox IV isoform 2, which operates in oxidative neuronal conditions. At all stages of disease, Cox IV-1 was absent from cells accumulating disease related PrP, suggesting that PrP aggregates may directly compromise normal mitochondrial function. Administration of Nano-PSO, a brain targeted antioxidant, to TgMHu2ME199K mice, reversed functional and biochemical mitochondrial functions to normal conditions regardless of the presence of misfolded PrP. Our results therefore indicate that in genetic prion disease, oxidative damage initiates long before clinical manifestations. These manifest only when aggregated PrP levels are too high for the compensatory mechanisms to sustain mitochondrial activity.
Asunto(s)
Mitocondrias/enzimología , Enfermedades por Prión/enzimología , Enfermedades por Prión/genética , Proteínas Priónicas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antioxidantes/administración & dosificación , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Aceites de Plantas/administración & dosificación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
TgMHu2ME199K mice, a transgenic line mimicking genetic prion disease, are born healthy and gradually deteriorate to a terminal neurological condition concomitant with the accumulation of disease-related PrP. To investigate whether transplantation of neural progenitor cells (NPCs) to these mice can delay disease aggravation, we first tested the properties of mutant PrP in homogenates and enriched NPCs from TgMHu2ME199K embryos, as compared to PrP in sick TgMHu2ME199K brains. Next, we tested the clinical effect of NPCs transplantation into newborn TgMHu2ME199K mice. We show that mutant PrP does not convert into a disease-related isoform while in progenitor cells. Most important, transplantation of both wild type and transgenic NPCs significantly delayed the progression of spontaneous prion disease in TgMHu2ME199K mice. While the strong clinical effect was not accompanied by a reduced accumulation of disease-related PrP, treated mouse brains presented a significant reduction in amyloid glycosaminoglycans and preservation of neurogenesis levels, indicating a strong neuroprotective effect. These results may encourage the investigation of new pathways for treatment in these terrible diseases.
Asunto(s)
Animales Recién Nacidos , Células-Madre Neurales/trasplante , Neuroprotección , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Enfermedades por Prión/genética , Enfermedades por Prión/prevención & control , Proteínas Amiloidogénicas/metabolismo , Animales , Autoinjertos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Glicosaminoglicanos/metabolismo , Glicosilación , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Neurogénesis , Enfermedades por Prión/metabolismoRESUMEN
We have shown previously that Nano-PSO, a nanodroplet formulation of pomegranate seed oil, delayed progression of neurodegeneration signs when administered for a designated period of time to TgMHu2ME199K mice, modeling for genetic prion disease. In the present work, we treated these mice with a self-emulsion formulation of Nano-PSO or a parallel Soybean oil formulation from their day of birth until a terminal disease stage. We found that long term Nano-PSO administration resulted in increased survival of TgMHu2ME199K lines by several months. Interestingly, initiation of treatment at day 1 had no clinical advantage over initiation at day 70, however cessation of treatment at 9months of age resulted in the rapid loss of the beneficial clinical effect. Pathological studies revealed that treatment with Nano-PSO resulted in the reduction of GAG accumulation and lipid oxidation, indicating a strong neuroprotective effect. Contrarily, the clinical effect of Nano-PSO did not correlate with reduction in the levels of disease related PrP, the main prion marker. We conclude that long term administration of Nano-PSO is safe and may be effective in the prevention/delay of onset of neurodegenerative conditions such as genetic CJD.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Aceites de Plantas/administración & dosificación , Sustancias Protectoras/administración & dosificación , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Progresión de la Enfermedad , Glicosaminoglicanos/metabolismo , Ratones Transgénicos , Oxidación-Reducción/efectos de los fármacos , Proteínas Gestacionales/metabolismo , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1002350.].
RESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1000977.].
RESUMEN
Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic proteins without an accompanying neurodegeneration pattern. The lack of a comprehensive model hinders efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice mimicking for genetic Creutzfeldt-Jacob disease as compared to age-matched wild-type mice. Mice exhibited a neurodegenerative process of progressive reduction in cortical neurons and synapses starting at age of 4-6 months, in accord with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with neurological disease progression, indicating these mice can serve as a model for neurodegenerative diseases.
RESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.
Asunto(s)
Antioxidantes/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Nanopartículas/química , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Lípidos/química , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Esclerosis Múltiple/patología , Oxidación-Reducción , Tamaño de la Partícula , Aceites de Plantas/administración & dosificación , Aceites de Plantas/farmacología , Aceites de Plantas/uso terapéutico , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
OBJECTIVES: Misfolding of key disease proteins to an insoluble state is associated with most neurodegenerative conditions, such as prion, Parkinson, and Alzheimer's diseases. In this work, and by studying animal models of multiple sclerosis, we asked whether this is also the case for myelin basic protein (MBP) in the late and neurodegenerative phases of demyelinating diseases. METHODS: To this effect, we tested whether MBP, an essential myelin component, present prion-like properties in animal models of MS, as is the case for Cuprizone-induced chronic demyelination or chronic phases of Experimental Autoimmune Encephalomyelitis (EAE). RESULTS: We show here that while total levels of MBP were not reduced following extensive demyelination, part of these molecules accumulated thereafter as aggregates inside oligodendrocytes or around neuronal cells. In chronic EAE, MBP precipitated concomitantly with Tau, a marker of diverse neurodegenerative conditions, including MS. Most important, analysis of fractions from Triton X-100 floatation gradients suggest that the lipid composition of brain membranes in chronic EAE differs significantly from that of naïve mice, an effect which may relate to oxidative insults and subsequently prevent the appropriate insertion and compaction of new MBP in the myelin sheath, thereby causing its misfolding and aggregation. INTERPRETATION: Prion-like aggregation of MBP following chronic demyelination may result from an aberrant lipid composition accompanying this pathological status. Such aggregation of MBP may contribute to neuronal damage that occurs in the progressive phase of MS.
RESUMEN
Neurodegenerative diseases generate the accumulation of specific misfolded proteins, such as PrP(Sc) prions or A-beta in Alzheimer's diseases, and share common pathological features, like neuronal death and oxidative damage. To test whether reduced oxidation alters disease manifestation, we treated TgMHu2ME199K mice, modeling for genetic prion disease, with Nano-PSO, a nanodroplet formulation of pomegranate seed oil (PSO). PSO comprises large concentrations of a unique polyunsaturated fatty acid, Punicic acid, among the strongest natural antioxidants. Nano-PSO significantly delayed disease presentation when administered to asymptomatic TgMHu2ME199K mice and postponed disease aggravation in already sick mice. Analysis of brain samples revealed that Nano-PSO treatment did not decrease PrP(Sc) accumulation, but rather reduced lipid oxidation and neuronal loss, indicating a strong neuroprotective effect. We propose that Nano-PSO and alike formulations may be both beneficial and safe enough to be administered for long years to subjects at risk or to those already affected by neurodegenerative conditions. FROM THE CLINICAL EDITOR: This team of authors report that a nanoformulation of pomegranade seed oil, containing high levels of a strong antioxidant, can delay disease onset in a mouse model of genetic prion diseases, and the formulation also indicates a direct neuroprotective effect.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Emulsiones/uso terapéutico , Lythraceae/química , Fármacos Neuroprotectores/uso terapéutico , Aceites de Plantas/uso terapéutico , Animales , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Emulsiones/química , Peroxidación de Lípido/efectos de los fármacos , Ratones , Fármacos Neuroprotectores/química , Oxidación-Reducción , Aceites de Plantas/química , Priones/metabolismo , Semillas/químicaRESUMEN
Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity.
Asunto(s)
Sistema Nervioso Central/patología , Síndrome de Creutzfeldt-Jakob/patología , Encefalomielitis Autoinmune Experimental/patología , Proteínas PrPSc/genética , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/inmunología , Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Expresión Génica , Humanos , Sistema Inmunológico , Ratones , Ratones Transgénicos , Proteínas PrPSc/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
While the conversion of PrP(C) into PrP(Sc) in the transmissible form of prion disease requires a preexisting PrP(Sc) seed, in genetic prion disease accumulation of disease related PrP could be associated with biochemical and metabolic modifications resulting from the designated PrP mutation. To investigate this possibility, we looked into the time related changes of PrP proteins in the brains of TgMHu2ME199K/wt mice, a line modeling for heterozygous genetic prion disease linked to the E200K PrP mutation. We found that while oligomeric entities of mutant E199KPrP exist at all ages, aggregates of wt PrP in the same brains presented only in advanced disease, indicating a late onset conversion process. We also show that most PK resistant PrP in TgMHu2ME199K mice is soluble and truncated (PrP(ST)), a pathogenic form never before associated with prion disease. We next looked into brain samples from E200K patients and found that both PK resistant PrPs, PrP(ST) as in TgMHu2ME199K mice, and "classical" PrP(Sc) as in infectious prion diseases, coincide in the patient's post mortem brains. We hypothesize that aberrant metabolism of mutant PrPs may result in the formation of previously unknown forms of the prion protein and that these may be central for the fatal outcome of the genetic prion condition.
Asunto(s)
Endopeptidasa K/metabolismo , Proteínas Mutantes/metabolismo , Enfermedades por Prión/genética , Priones/metabolismo , Animales , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/genética , Heterocigoto , Homocigoto , Humanos , Cinética , Membranas/patología , Ratones , Ratones Transgénicos , Enfermedades por Prión/patología , Priones/química , Estructura Cuaternaria de Proteína , SolubilidadRESUMEN
Since preventive treatments for prion disease require early identification of subjects at risk, we searched for surrogate peripheral markers characterizing the asymptomatic phases of such conditions. To this effect, we subjected blood mRNA from E200K PrP CJD patients and corresponding family members to global arrays and found that the expression of Snord3A, a non-coding RNA transcript, was elevated several times in CJD patients as compared to controls, while asymptomatic carriers presented intermediate Snord3A levels. In the brains of TgMHu2ME199K mice, a mouse model mimicking for E200K CJD, Snord 3A levels were elevated in an age and disease severity dependent manner, as was the case for brains of these mice in which disease was exacerbated by copper administration. Snord3A expression was also elevated in scrapie infected mice, but not in PrP(0/0) mice, indicating that while the expression levels of this transcript may reflect diverse prion etiologies, they are not related to the loss of PrP(C)'s function. Elevation of Snord3A was consistent with the activation of ATF6, representing one of the arms of the unfolded protein response system. Indeed, SnoRNAs were associated with reduced resistance to oxidative stress, and with ER stress in general, factors playing a significant role in this and other neurodegenerative conditions. We hypothesize that in addition to its function as a disease marker, Snord3A may play an important role in the mechanism of prion disease manifestation and progression.