Biology and genetics of prions causing neurodegeneration.

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in ß-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.

Identification of amyloidogenic peptides via optimized integrated features space based on physicochemical properties and PSSM.

At present, the identification of amyloid becomes more and more essential and meaningful. Because its mis-aggregation may cause some diseases such as Alzheimer's and Parkinson's diseases. This paper focus on the classification of amyloidogenic peptides and a novel feature representation called PhyAve_PSSMDwt is proposed. It includes two parts. One is based on physicochemical properties involving hydrophilicity, hydrophobicity, aggregation tendency, packing density and H-bonding which extracts 15-dimensional features in total. And the other is 60-dimensional features through recursive feature elimination from PSSM by discrete wavelet transform. In this period, sliding window is introduced to reconstruct PSSM so that the evolutionary information of short sequences can still be extracted. At last, the support vector machine is adopted as a classifier. The experimental result on Pep424 dataset shows that PSSM's information makes a great contribution on performance. And compared with other existing methods, our results after cross-validation increase by 3.1%, 3.3%, 0.136 and 0.007 in accuracy, specificity, Matthew's correlation coefficient and AUC value, respectively. It indicates that our method is effective and competitive.

The zipper groups of the amyloid state of proteins.

Fibrous proteins in the amyloid state are found both associated with numerous diseases and in the normal functions of cells. Amyloid fibers contain a repetitive spine, commonly built from a pair of ß-sheets whose ß-strands run perpendicular to the fiber direction and whose side chains interdigitate, much like the teeth of a zipper. In fiber spines known as homosteric zippers, identical protein segments sharing identical packing environments make the two ß-sheets. In previous work based on atomic resolution crystal structures of homosteric zippers derived from a dozen proteins, the symmetries of homosteric zippers were categorized into eight classes. Here, it is shown through a formal derivation that each homosteric zipper class corresponds to a unique set of symmetry groups termed `zipper groups'. Furthermore, the eight previously identified classes do not account for all of the 15 possible zipper groups, which may be categorized into the complete set of ten classes. Because of their foundations in group theory, the 15 zipper groups provide a mathematically rigorous classification for homosteric zippers.

Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.

The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.

Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases.

A common feature of many neurodegenerative diseases is the deposition of ß-sheet-rich amyloid aggregates formed by proteins specific to these diseases. These protein aggregates are thought to cause neuronal dysfunction, directly or indirectly. Recent studies have strongly implicated cell-to-cell transmission of misfolded proteins as a common mechanism for the onset and progression of various neurodegenerative disorders. Emerging evidence also suggests the presence of conformationally diverse 'strains' of each type of disease protein, which may be another shared feature of amyloid aggregates, accounting for the tremendous heterogeneity within each type of neurodegenerative disease. Although there are many more questions to be answered, these studies have opened up new avenues for therapeutic interventions in neurodegenerative disorders.

Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 6-10, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils.

On typing amyloidosis using immunohistochemistry. Detailled illustrations, review and a note on mass spectrometry.

Every amyloid disease needs to be assessed for chemical composition of its amyloid because amyloid is pathogenetically diverse and each of the chemical amyloid types requires a different therapy. Basically four different approaches are being applied for typing of amyloid using immunohistochemistry, immunochemistry, mass spectrometry and chemistry. It is shown here how an easy immunohistochemical procedure has been developed over the years that can be used to classify specifically amyloid proteins for clinico-pathologic routine use. A larger number of tissues with chemically or immunochemically typed amyloids served as prototypes for developing a set of validated amyloid antibodies. These were examined for their performance to classify a larger number of tissues of patients submitted to us and other institutions allowing independent evaluation. The data reveal that out of 663 patients, including 15 different amyloid types, all 119 prototype Amyloids (100%) have been classified correctly and 97.9% of consecutive 581 unknown amyloid tissues submitted for typing to our laboratory of whom 37 became later prototypes. Twelve samples (2.1%) could not be classified. By using appropriate amyloid antibodies in a comparative manner, this procedure is accurate. It identifies the respective amyloid type and excludes simultaneously other amyloids. Its improved performance leads to an accurate amyloid diagnosis in most cases and provides a diagnostic marker which is independend of any other information for therapeutic considerations. These results can be obtained within a day in institutes competent in performing immunohistochemistry. This is the first report on immunhistochemical typing of amyloid providing detailed illustrations of the original results for training purposes. When the immunohistochemical method presented here was compared with mass spectrometry, a more recent method for amyloid typing, the advantages and failures of both methods became apparent in an international blinded comparison.

Proteomic typing of amyloid deposits in systemic amyloidoses.

Amyloidoses are characterized by the presence of extracellular amyloid deposits, constituted by fibrillar aggregates of misfolded proteins. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been detected as causative agents of human amyloidoses, 14 of which associated with systemic forms. Unequivocal typing of the amyloid deposits is a key step in the management of these diseases. Existing drawbacks of traditional, immunohistochemistry-based techniques have driven the search for alternative solutions for direct amyloid typing. Proteomics indicates the comprehensive study of the proteins in a biological sample, centered on analysis by mass spectrometry. The great potential of this approach in describing the composition of amyloid deposits and in studying the molecular features of the amyloidogenic precursors has become immediately clear and the introduction of proteomics in the clinical practice has revolutionized the field of amyloid typing. This review provides a critical overview of the various approaches that have been proposed in this specific context, along with a brief description of the proteomic methods for assessment of the circulating amyloidogenic proteins.