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Neurobiology of Disease Jan 2024Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrP) spontaneously misfolds and...
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrP) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6 and Stx6 mice differed by 12 days relative to wildtype. Similarly, in Stx6 mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6 animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6 mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.
Topics: Mice; Humans; Animals; Creutzfeldt-Jakob Syndrome; Prions; Genome-Wide Association Study; Mice, Transgenic; Brain; Prion Diseases; Qa-SNARE Proteins
PubMed: 37996040
DOI: 10.1016/j.nbd.2023.106363 -
Brain : a Journal of Neurology Nov 2023The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the...
The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.
Topics: Mice; Animals; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Epitopes; Phenotype; Protein Folding; Disease Models, Animal; Mice, Transgenic
PubMed: 37394908
DOI: 10.1093/brain/awad222 -
Science (New York, N.Y.) Mar 2024Can the course of fatal prion diseases be changed by removing the protein before it goes bad?
Can the course of fatal prion diseases be changed by removing the protein before it goes bad?
Topics: Humans; Prion Diseases; Prions; Mutation; Zinc Fingers
PubMed: 38513035
DOI: 10.1126/science.adp3043 -
Alzheimer's & Dementia : the Journal of... Jan 2024Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for...
INTRODUCTION
Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored.
METHODS
We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD).
RESULTS
Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001).
DISCUSSION
Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.
Topics: Humans; Alzheimer Disease; tau Proteins; Creutzfeldt-Jakob Syndrome; Brain; Biomarkers; Diagnosis, Differential; Amyloid beta-Peptides
PubMed: 37858957
DOI: 10.1002/alz.13516 -
Biophysical Chemistry Nov 2023Numerous neurological disorders, including prion, Parkinson's, and Alzheimer's disease (AD), are identified as being caused by alterations in protein conformation,...
Numerous neurological disorders, including prion, Parkinson's, and Alzheimer's disease (AD), are identified as being caused by alterations in protein conformation, aggregation, and metal ion dyshomeostasis. Recent years have seen a significant increase in the exploration and study of natural products (NPs) from plant and microbial sources for their therapeutic potential against several diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. In this study, we have examined the effect of two NPs, cycloastragenol (CAG) and punicalagin (PCG), on the metal-induced oligomerization and aggregation of Aβ and PrP peptides. The peptide aggregation and inhibitory properties of both NPs were examined by the thioflavin-T (ThT) assay, MALDI-TOF, circular dichroism (CD) spectroscopy, and transmission electron microscopy (TEM). Among the two NPs, PCG significantly binds to the peptides, chelates metal ions (Cu and Zn), inhibits peptide aggregation, substantially reduces oxidative stress, and controls the production of reactive oxygen species (ROS). Both NPs exhibited low cytotoxicity and prominently mitigated peptide-mediated cell cytotoxicity in hippocampal neuronal HT-22 cells by covalent bonding and hydrophobic interactions.
PubMed: 37734278
DOI: 10.1016/j.bpc.2023.107108 -
Neural Regeneration Research Jun 2024Alzheimer's disease is characterized by two major neuropathological hallmarks-the extracellular β-amyloid plaques and intracellular neurofibrillary tangles consisting...
Alzheimer's disease is characterized by two major neuropathological hallmarks-the extracellular β-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein. Recent studies suggest that dysregulation of the microtubule-associated protein Tau, especially specific proteolysis, could be a driving force for Alzheimer's disease neurodegeneration. Tau physiologically promotes the assembly and stabilization of microtubules, whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers, resulting in them gaining prion-like characteristics. In addition, Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner. This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments, investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease, and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.
PubMed: 37905868
DOI: 10.4103/1673-5374.385853 -
Journal of Molecular Biology Dec 2023Tauopathies, synucleinopathies, Aβ amyloidosis, TDP-43 proteinopathies, and prion diseases- these neurodegenerative diseases have in common the formation of amyloid... (Review)
Review
Tauopathies, synucleinopathies, Aβ amyloidosis, TDP-43 proteinopathies, and prion diseases- these neurodegenerative diseases have in common the formation of amyloid filaments rich in cross-β sheets. Cryo-electron microscopy now permits the visualization of amyloid assemblies at atomic resolution, ushering a wide range of structural studies on several of these poorly understood amyloidogenic proteins. Amyloids are polymorphic with minor modulations in reaction environment affecting the overall architecture of their assembly, making amyloids an extremely challenging venture for structure-based therapeutic intervention. In 2017, the first cryo-EM structure of tau filaments from an Alzheimer's disease-affected brain established that in vitro assemblies might not necessarily reflect the native amyloid fold. Since then, brain-derived amyloid structures for several proteins across many neurodegenerative diseases have uncovered the disease-relevant amyloid folds. It has now been shown for tauopathies, synucleinopathies and TDP-43 proteinopathies, that distinct amyloid folds of the same protein might be related to different diseases. Salient features of each of these brain-derived folds are discussed in detail. It was also recently observed that seeded aggregation does not necessarily replicate the brain-derived structural fold. Owing to high throughput structure determination, some of these native amyloid folds have also been successfully replicated in vitro. In vitro replication of disease-relevant filaments will aid development of imaging ligands and defibrillating drugs. Towards this direction, recent high-resolution structures of tau filaments with positron emission tomography tracers and a defibrillating drug are also discussed. This review summarizes and celebrates the recent advancements in structural understanding of neuropathological amyloid filaments using cryo-EM.
Topics: Humans; tau Proteins; Cryoelectron Microscopy; Synucleinopathies; Alzheimer Disease; Tauopathies; Amyloid; Neurodegenerative Diseases; TDP-43 Proteinopathies; Amyloidogenic Proteins
PubMed: 37949311
DOI: 10.1016/j.jmb.2023.168361 -
Cellular and Molecular Neurobiology Aug 2023Prion' is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The... (Review)
Review
Prion' is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria. Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation. Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequenct production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manesfestions post-acute viral infection.
Topics: Humans; Animals; Prions; Post-Acute COVID-19 Syndrome; Reactive Oxygen Species; COVID-19; SARS-CoV-2; Mammals
PubMed: 36977809
DOI: 10.1007/s10571-023-01342-8 -
MedRxiv : the Preprint Server For... Dec 2023Genetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development....
IMPORTANCE
Genetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development. Preclinical proofs of concept indicate that treatment before symptoms will offer outsize benefit. Though early treatment paradigms will be informed by the longitudinal biomarker trajectory of mutation carriers, to date limited cases have been molecularly tracked from the presymptomatic phase through symptomatic onset.
OBJECTIVE
To longitudinally characterize disease-relevant cerebrospinal fluid (CSF) and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion, alongside non-converters and healthy controls.
DESIGN SETTING AND PARTICIPANTS
This single-center longitudinal cohort study has followed 41 mutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenic variants; all subjects were asymptomatic at first visit and returned roughly annually. Four at-risk individuals experienced prion disease onset during the study.
MAIN OUTCOMES AND MEASURES
RT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL) total tau (t-tau), and beta synuclein were measured in CSF. Glial fibrillary acidic protein (GFAP) and NfL were measured in plasma.
RESULTS
We observed RT-QuIC seeding activity in the CSF of three E200K carriers prior to symptom onset and death, while the CSF of one P102L carrier remained RT-QuIC negative through symptom conversion. The prodromal window of RT-QuIC positivity was one year long in an E200K individual homozygous (V/V) at PRNP codon 129 and was longer than two years in two codon 129 heterozygotes (M/V). Other neurodegenerative and neuroinflammatory markers gave less consistent signal prior to symptom onset, whether analyzed relative to age or individual baseline. CSF PrP was longitudinally stable (mean CV 10%) across all individuals over up to 6 years, including at RT-QuIC positive timepoints.
CONCLUSION AND RELEVANCE
In this study, we demonstrate that at least for the E200K mutation, CSF prion seeding activity may represent the earliest detectable prodromal sign, and that its prognostic value may be modified by codon 129 genotype. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.
PubMed: 38196583
DOI: 10.1101/2023.12.18.23300042 -
Cytoskeleton (Hoboken, N.J.) Jan 2024Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to... (Review)
Review
Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to stardom as a central player in neurodegenerative disease, therapeutic efforts have largely been targeted toward cytoskeletal changes. While some studies hinted toward non-cytoskeletal roles for tau, it is only fairly recently that these ideas have begun to receive considerable attention. Many new binding partners for tau have been identified, including DNA, RNA, RNA-binding proteins, some receptors, and other tau molecules. The diversity of tau binding partners coupled with the discovery of tau other than axonal compartments such as nucleus, dendrites, and synapses have led to the proposal of novel functions for tau in roles such as nuclear stability, cell signaling, transcriptional processing, and protein synthesis. Tau self-assembly in particular has made an impact, leading to the hypothesis that a prion-like function of hyperphosphorylated tau is central to tauopathies. With tau emerging as a multifaceted protein that operates in many parts of the cell and with many molecular partners, the field of tau biology is primed for discoveries that can provide new perspectives on both the unique biochemistry of tau and the nature of devastating neurological diseases.
Topics: Humans; tau Proteins; Neurodegenerative Diseases; Carrier Proteins; Microtubules; Neurons; Phosphorylation
PubMed: 37819542
DOI: 10.1002/cm.21795