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Published in Ibrahim Natalwala, Ammar Natalwala, E Glucksman, MCQs in Neurology and Neurosurgery for Medical Students, 2022
Ibrahim Natalwala, Ammar Natalwala, E Glucksman
Creutzfeldt-Jakob disease is a prion disease that causes a rapidly progressive (weeks to months) dementia and early death. It can be acquired through ingestion of beef from cattle affected by mad cow disease. Prion diseases are caused by the conversion of a normal cellular protein termed prion protein to a beta-pleated form. The beta-pleated form resists degradation by proteases and its accumulation results in a spongiform encephalopathy. Multiple cysts with an absence of inflammatory cells on biopsy are characteristic.5,6
Dementia
Published in Henry J. Woodford, Essential Geriatrics, 2022
CJD is caused by a prion. In such disorders, a cellular prion protein (PrPC) becomes pathogenic by misfolding into a harmful form (PrPSC).39 This is then capable of inducing changes in other prion proteins with a resultant cascade and accumulation of protein aggregates (seeFigure 6.8).53 Pathological changes include spongiform degeneration and astrogliosis.39 It is most commonly sporadic in nature (85%) but familial (10–15%) and infectious forms (< 5%) also exist.54 The infectious forms include a new variant (nvCJD) caused by the ingestion of infected animal products. The sporadic form has a mean age of onset of 62 years and runs a short course (mean survival five months).54,55 Overall it has an incidence of around one per million per year but this figure rises to around five per million in those over the age of 60.39 Key clinical features are listed below:A rapidly progressive subcortical dementiaMyoclonusAtaxiaPyramidal or extrapyramidal signs
Epidemiology and subtypes of dementia
Published in Marjolein de Vugt, Janet Carter, Understanding Young Onset Dementia, 2021
Prion diseases are associated with the accumulation of an abnormal, partially protease‐resistant isoform of prion protein (PrP) in the brain (Mead et al., 2006). PrP is a normal cell surface glycoprotein found in healthy people, but the disease‐related isoform, PrPSc, is derived from its normal cellular precursor, PrPC, by a post‐translational process that involves conformational change and aggregation referred to as protein misfolding (Collinge, 2001; Sigurdson et al., 2019).
Emerging role of metabolomics in protein conformational disorders
Published in Expert Review of Proteomics, 2021
Nimisha Gupta, Sreelakshmi Ramakrishnan, Saima Wajid
In recent years, metabolomics has become a widely used tool to detect PCDs. PCDs are believed to be caused by protein misfolding that gives rise to off-pathway aggregates in the form of amyloid fibrils. The aggregates get deposited in tissues of multiple organs, such as the heart, liver, kidney, and brain. Protein misfolding usually leads to harmful outcomes, resulting in toxicity and eventually causing death [9–11]. Amyloid fibrils are insoluble and thread-like protein aggregates that may cause various human degenerative disorders, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and prion disease, each of which is associated with a specific protein. Alzheimer’s disease is linked with progressive deposition of Amyloid β-peptides (Aβ) in the brain. Parkinson’s disease is characterized by the accumulation of misfolded alpha-synuclein along the cerebral axis. Huntington’s disease is caused due to CAG repeat expansion in the htt (huntingtin) gene [12–14]. The prion diseases are caused due to misfolding of cellular prion protein (PrPC) [15]. Our study aimed to find the variations in metabolites and explore the interrelated metabolic pathways in various proteinopathies.
Progress regarding the context-of-use of tau as biomarker of Alzheimer’s disease and other neurodegenerative diseases
Published in Expert Review of Proteomics, 2021
Nicole Campese, Giovanni Palermo, Claudia Del Gamba, Maria Francesca Beatino, Alessandro Galgani, Elisabetta Belli, Eleonora Del Prete, Alessandra Della Vecchia, Andrea Vergallo, Gabriele Siciliano, Roberto Ceravolo, Harald Hampel, Filippo Baldacci
However, these ultrasensitive techniques fail in discriminating different tridimensional conformations of tau (e.g. 3R vs 4R tau). Nevertheless, the selective identification of different tau seeds represents a critical issue to understand the pathophysiology of the primary tauopathies. Based also on the hypothesis of a prion-like transcellular propagation of tau, real-time quaking-induced conversion (RT-QuIC) and protein misfolded cycle amplification (PMCA) have been successfully applied in NDDs [39]. These techniques were initially developed for the detection of prion proteins in Creutzfeldt-Jakob disease. RT-QuIC uses recombinant protein substrates undergoing shaking and incubation cycles to quantify seeding activity of prions (e.g. PrP) and prion-like proteins, such as α-synuclein (α-syn) and tau strains [40]. Similarly, in PMCA seeding activity of substrates derived from brain homogenates or recombinant proteins is amplified by cycles of sonification, enabling a sensitive detection and a selective amplification of specific protein seeds [39].
Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials
Published in Expert Opinion on Emerging Drugs, 2020
Andrea Barp, Francesca Gerardi, Andrea Lizio, Valeria Ada Sansone, Christian Lunetta
Prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology. The neuropathological similarities of prion diseases with other neurodegenerative diseases include substantial neuronal loss, accumulation of proteins into aggregates, gliosis, and general cerebral atrophy [62]. Evidence from in vitro, cell culture, and in vivo studies has provided strong evidence to support the involvement of a prion-like mechanism in ALS. Firstly, ALS is known to start focally and spread to other regions in a neuroanatomic manner [63]; secondly, the accumulation of misfolded proteins is the defining hallmark of neurodegenerative proteinopathies including ALS [64]; thirdly, ALS shows the hallmarks of prion-like propagation owing to the spread of pathology throughout affected tissues [49]. Aggregation of misfolded proteins can cause toxicity either by loss‐of‐function or gain‐of‐function mechanisms. Furtherly, many of the ALS-linked proteins contain prion-like domains that are involved in stress granule formation or dynamics, including TDP-43, FUS, TAF15, ESWR1, hnRNPA1, and hnRNPA2B1. Prion-like domains are thought to be vital for the reversible assembly of stress granules due to their capacity for forming multiple transient weak interactions [65]. Due to different evidence the possibility of prion-like propagation theories influencing the pathomechanisms of ALS development cannot be ruled out [64].