Abstract
A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.
Highlights
In recent years, prion-like spread of misfolded, self-propagating protein aggregates was observed in a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, amyloid lateral sclerosis (ALS) and others [1,2]
This article summarizes recent studies that aimed at establishing a link between strainspecific structure, Posttranslational modifications (PTMs) and disease phenotype
Protein isoforms with the PTMs that create constraints incompatible with a strain-specific structure are expected to be excluded from conversion
Summary
Prion-like spread of misfolded, self-propagating protein aggregates was observed in a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, amyloid lateral sclerosis (ALS) and others [1,2]. The diversity of clinical phenotypes is attributed to the ability of amyloidogenic proteins or peptides associated with a particular disease to acquire multiple, alternative, conformationally distinct, self-replicating states [10,11,12]. The spectrum of strains could be limited to only those structures which are capable of recruiting polypeptide chains regardless of the nature and position of PTMs in individual polypeptides [21] If this is the case, most polypeptide molecules would be eligible for conversion regardless of the degree and nature of their PTMs; strain structural diversity is expected to be limited to only a very few structures [21]. Polypeptides with a subset of PTMs which can fit into a strain-specific structure can be successfully recruited [21] If this is the case, a greater structural diversity is expected; only a sub-population of substrate molecule will be eligible for conversion by each particular strain [21]. The mechanism on selective recruitment is expected to result in a strain-specific pattern of PTMs associated with each strain [21]
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