Close patient observation and electroencephalography play an important role in the diagnosis of rare diseases. Presentation of a case of Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease is a rare, progressive spongiform encephalopathy caused by infectious proteins called prions. It is characterised by rapidly progressive dementia accompanied by cerebellar, visual, extrapyramidal, and pyramidal symptoms, as well as myoclonus and mutism in later stage of the disease. The most common type is sporadic Creutzfeldt– Jakob disease, accounting for 85% of all cases. Treatment of the disease is symptomatic. An important role in making the diagnosis is attributed to the observation of the patient and electroencephalography, showing characteristic cyclical discharges. We present the case of a patient whose first symptoms were psychiatric in nature, and who was diagnosed with Creutzfeldt–Jakob disease based on careful observation, presence of myoclonus, and repeated electroencephalography examinations in which typical 1–2 seconds of sharp and slow wave discharges appeared. By presenting this case of severe progressive encephalopathy, we would like to highlight the fact that even in the age of modern diagnostic methods, electroencephalography, which has been in use for many years, may be crucial in the diagnostic process. We would also like to point out that the initial symptoms of Creutzfeldt–Jakob disease may suggest a psychiatric disorder.

Structures of Pathological and Functional Amyloids and Prions, a Solid-State NMR Perspective

Infectious proteins or prions are a remarkable class of pathogens, where pathogenicity and infectious state correspond to conformational transition of a protein fold. The conformational change translates into the formation by the protein of insoluble amyloid aggregates, associated in humans with various neurodegenerative disorders and systemic protein-deposition diseases. The prion principle, however, is not limited to pathogenicity. While pathological amyloids (and prions) emerge from protein misfolding, a class of functional amyloids has been defined, consisting of amyloid-forming domains under natural selection and with diverse biological roles. Although of great importance, prion amyloid structures remain challenging for conventional structural biology techniques. Solid-state nuclear magnetic resonance (SSNMR) has been preferentially used to investigate these insoluble, morphologically heterogeneous aggregates with poor crystallinity. SSNMR methods have yielded a wealth of knowledge regarding the fundamentals of prion biology and have helped to solve the structures of several prion and prion-like fibrils. Here, we will review pathological and functional amyloid structures and will discuss some of the obtained structural models. We will finish the review with a perspective on integrative approaches combining solid-state NMR, electron paramagnetic resonance and cryo-electron microscopy, which can complement and extend our toolkit to structurally explore various facets of prion biology.

Artificial Intelligence-driven drug repurposing and structural biology for SARS-CoV-2

It has been said that COVID-19 is a generational challenge in many ways. But, at the same time, it becomes a catalyst for collective action, innovation, and discovery. Realizing the full potential of artificial intelligence (AI) for structure determination of unknown proteins and drug discovery are some of these innovations. Potential applications of AI include predicting the structure of the infectious proteins, identifying drugs that may be effective in targeting these proteins, and proposing new chemical compounds for further testing as potential drugs. AI and machine learning (ML) allow for rapid drug development including repurposing existing drugs. Algorithms were used to search for novel or approved antiviral drugs capable of inhibiting SARS-CoV-2. This paper presents a survey of AI and ML methods being used in various biochemistry of SARS-CoV-2, from structure to drug development, in the fight against the deadly COVID-19 pandemic. It is envisioned that this study will provide AI/ML researchers and the wider community an overview of the current status of AI applications particularly in structural biology, drug repurposing and development and motivate researchers in harnessing AI potentials in the fight against COVID-19.

Mechanisms for Curing Yeast Prions

Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing.

How Do Yeast Cells Contend with Prions?

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.

Cellular and Molecular Mechanisms of Prion Disease

Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.

Selected Concepts

This chapter on “Selected Concepts” examines the evolution of neurological concepts during the modern era. Examples presented include the concepts of transient ischemic attack, disconnection syndrome, thoracic outlet syndrome, and Wilbrand’s knee. Over the past half century, neurology has witnessed great technological advances. Newer scientific methods, such as MRI scanning, have led to new knowledge that has necessitated changes in neurologic concepts. During recent decades, new concepts have emerged. Infectious proteins, antibody-mediated brain disease, channelopathies, and the glymphatic system are relatively new ideas, and we cannot foresee how our understanding of these concepts will be advanced or modified in the coming decades.

Autophagy protects against de novo formation of the [PSI+] prion in yeast

Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [ PSI+], which is the prion form of the yeast Sup35 translation termination factor. Autophagy is a cellular degradation system, and preventing autophagy by mutating its core components elevates the frequency of spontaneous [ PSI+] formation. Conversely, increasing autophagic flux by treating cells with the polyamine spermidine suppresses prion formation in mutants that normally show a high frequency of de novo prion formation. Autophagy also protects against the de novo formation of another prion, namely the Rnq1/[ PIN+] prion, which is not related in sequence to the Sup35/[ PSI+] prion. We show that growth under anaerobic conditions in the absence of molecular oxygen abrogates Sup35 protein damage and suppresses the high frequency of [ PSI+] formation in an autophagy mutant. Autophagy therefore normally functions to remove oxidatively damaged Sup35, which accumulates in cells grown under aerobic conditions, but in the absence of autophagy, damaged/misfolded Sup35 undergoes structural transitions favoring its conversion to the propagatable [ PSI+] form.

Secondary nucleation overcomes seeding template in amyloid-like fibril formation

Prions are infectious proteins where the same protein may express distinct strains. The strains are enciphered by different misfolded conformations. Strain-like phenomena have also been reported in a number of other amyloid-forming proteins. One of the features of amyloid strains is the ability to self-propagate, maintaining a constant set of physical properties despite being propagated under conditions different from those that allowed initial formation of the strain. Here we report a cross-seeding experiment using strains formed under different conditions. Using high concentrations of seeds results in rapid elongation and new fibrils preserve the properties of the seeding fibrils. At low seed concentrations secondary nucleation plays the major role and new fibrils gain properties predicted by the environment rather than the structure of the seeds. Our findings could explain conformational switching between amyloid strains observed in a wide variety of in vivo and in vitro experiments.

Secondary nucleation overcomes seeding template in amyloid-like fibril formation

Prions are infectious proteins where the same protein may express distinct strains. The strains are enciphered by different misfolded conformations. Strain-like phenomena have also been reported in a number of other amyloid-forming proteins. One of the features of amyloid strains is the ability to self-propagate, maintaining a constant set of physical properties despite being propagated under conditions different from those that allowed initial formation of the strain. Here we report a cross-seeding experiment using strains formed under different conditions. Using high concentrations of seeds results in rapid elongation and new fibrils preserve the properties of the seeding fibrils. At low seed concentrations secondary nucleation plays the major role and new fibrils gain properties predicted by the environment rather than the structure of the seeds. Our findings could explain conformational switching between amyloid strains observed in a wide variety of in vivo and in vitro experiments.