Abstract
A system of amyloid fibril nomenclature based on the chemical identity of the amyloid fibril forming protein is recommended. This system has been in use for approximately 40 years, but current literature remains confused with clinical and histochemical designations used when the amyloid disease processes were poorly understood. To be designated an amyloid fibril protein, the protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarisation microscopy. Furthermore, the protein must have been unambiguously characterised by protein sequence analysis (DNA sequencing in the case of familial diseases). Current nomenclature lists of 27 human and nine animal fibril proteins are provided together with a list of eight inclusion bodies that exhibit some of the properties of amyloid fibrils.
Background
The Nomenclature Committee of the International Society of Amyloidosis met in conjunction with the XII International Symposium on Amyloidosis (Rome, Italy, 18–21 April 2010) to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the nomenclature list ().
Table I. Amyloid fibril proteins and their precursors in humans.*
The need for widespread adoption of a logical and clearly understood nomenclature for amyloid fibril proteins has grown more urgent as our understanding of the chemical diversity of amyloid fibril proteins has increased. To date, there are 27 known extracellular fibril proteins in human (), at least nine of which have been studied in animal models (). This large number of naturally occurring amyloid fibril proteins underlies the need for consistent use of standardised nomenclature to facilitate the type of clear communication that will promote advancements in our understanding of amyloid disease processes and will hasten timely and appropriate treatments for patients.
Table II. Amyloid fibril proteins and their precursors in animals.
A large number of intracellular protein inclusions have been reported, at least one of which, the neurofibrillary tangles, has fibrillar structure, a cross β-sheet X-ray diffraction pattern, binds Congo red and exhibits green birefringence when viewed by polarisation microscopy (). The tangles are thus ‘intracellular amyloid’, although they have not been included on the nomenclature list. Other inclusions may have some, but not all, of these properties, e.g. inclusion bodies within muscle fibers of inclusion body myositis, which are stained by Congo red, exhibit green birefringence and are immunoreactive with anti-amyloid-β.
Table III. Intracellular inclusions with known biochemical composition, with or without amyloid properties.
Amyloid fibril protein nomenclature
The established amyloid fibril nomenclature is based on the chemical nature of the fibril protein, which is designated protein A and followed by a suffix that is an abbreviated form of the parent or precursor protein name. For example, when amyloid fibrils are derived from immunoglobulin light chains, the amyloid fibril is AL and the disease is AL amyloidosis. Variants are named according to the mutation in the gene for the protein, e.g. ATTRV30M or ALysI56T ( and ). The amyloidosis is then named after the protein, e.g. AL amyloidosis or ATTRV30M amyloidosis. This nomenclature has been adopted by the World Health Organization [Citation1] and consistently recommended by the ISA Nomenclature Committee [Citation2–8].
Recommendations
The ISA Nomenclature Committee urges those involved in amyloid research and treatment to adopt the above standardised nomenclature, keeping in mind the following questions:
What is an amyloid fibril?
An insoluble protein fibril that is deposited, mainly, in the extracellular spaces of organs and tissues as a result of a sequence of changes in protein folding that results in a condition known as amyloidosis.
Is the candidate protein an amyloid fibril protein?
An amyloid fibril protein occurs in tissue deposits as rigid, non-branching fibrils approximately 10 nm in diameter. The fibrils bind the dye Congo red and exhibit green birefringence when viewed by polarisation microscopy. When isolated and analysed by X-ray diffraction, the fibrils exhibit a characteristic cross β diffraction pattern.
The designation ‘amyloid’, first used in botany, was applied by Virchow, originally to corpora amylacea in the brain and later for the tissue deposits of systemic amyloidosis. Subsequently, the concept of amyloid was expanded to denote diverse localised tissue deposits (e.g. in Alzheimer's disease or type 2 diabetes) with similar homogeneous appearance in light microscopy and with the same tinctorial and physical properties. The definition of amyloid has now been further widened in that it is regularly used by biochemists for synthetic protein fibrils with some amyloid properties. In order to avoid confusion, the ISA Nomenclature Committee has recommended the use of ‘amyloid-like’ for synthetic fibrils [Citation8].
What is the chemical identity of the amyloid fibril protein?
An amyloid fibril protein, to appear in the official nomenclature list, must have been unambiguously characterised by protein sequence analysis (DNA sequencing in the case of familial diseases) and described in a peer-reviewed journal.
Why is it important to determine the chemical identity of an amyloid fibril protein in a patient with systemic amyloidosis?
More than one type of amyloid fibril protein can be deposited in a given tissue. For example, the familial amyloidoses are chemically and clinically heterogeneous and are associated with nomenclature harkening back to times when the nature of the fibril was unknown that is still in use. An example of this early nomenclature is familial amyloid polyneuropathy. It is important to use the accepted nomenclature, e.g. ATTRV30M and ATTRY78F, thus avoiding confusion with the more frequently occurring AL amyloidosis, for which the treatment plan would be markedly different.
Why is amyloid precursor protein (APP) used for the precursor of amyloid-β (Aβ)?
The use of amyloid precursor protein (APP), for APP, occurs widely in the neuroscience literature. This term could, of course, refer to any of the 27 amyloid fibril protein precursors. The correct nomenclature is AβPP; this is recommended by the ISA Nomenclature Committee and the journal Amyloid.
Why are Greek letters sometimes used for variants of serum amyloid A (SAA), some of which are precursors of amyloid A (AA)?
The ISA Nomenclature Committee recommended in 1999 [Citation9] that allelic variants of human SAA proteins should be designated as SAA1.1, 1.2, 1.3 and 1.4 instead of SAA1α, β, γ and δ. The use of Greek letters should be discontinued.
Do amyloid fibrils serve biological function(s)?
Another nomenclature related question has emerged with the use of the concept ‘functional amyloid’. Structurally robust, protease resistant β-sheet fibrillar assemblies are widely used in nature, particularly in invertebrates, e.g. as bacterial biofilms. In addition, it has been suggested that some human structures, such as the p-mel framework in melanosomes and the organisation of polypeptide hormones when stored in secretory vesicles, have an amyloid fibril structure [Citation10–12]. These more broadly applied circumstances have made it increasingly important to use clear definitions when using the word ‘amyloid’.
Newly identified amyloid fibril protein
The ISA Nomenclature Committee considered candidate newly identified amyloid fibril proteins and voted to include ALect2, first identified in renal amyloid deposits as reported by the Benson Laboratory [Citation13].
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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